 |
|
Rifampin and Rifabutin Drug Interactions
An Update
Christopher K. Finch, PharmD;
Cary R. Chrisman, PharmD;
Anne M. Baciewicz, PharmD, MBA;
Timothy H. Self, PharmD
Arch Intern Med. 2002;162:985-992.
ABSTRACT
| |
Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes.
A few examples of well-documented clinically significant interactions include
interactions with warfarin, oral contraceptives, cyclosporine, glucocorticoids,
ketoconazole or itraconazole, theophylline, quinidine sulfate, digitoxin or
digoxin, verapamil hydrochloride, human immunodeficiency virus–related
protease inhibitors, zidovudine, delavirdine mesylate, nifedipine, and midazolam.
Recent reports have demonstrated clinically relevant interactions with numerous
other drugs, such as buspirone hydrochloride, zolpidem tartrate, simvastatin,
propafenone hydrochloride, tacrolimus, ondansetron hydrochloride, and opiates.
Rifabutin reduces serum concentrations of antiretroviral agents, but less
so than rifampin. To avoid a reduced therapeutic response, therapeutic failure,
or toxic reactions when rifampin is added to or discontinued from medication
regimens, clinicians need to be cognizant of these interactions. Enhanced
knowledge of known interactions will continue to develop, including research
on the induction of specific cytochrome P-450 isoenzymes and on the importance
of the P-glycoprotein transport system. New rifampin and rifabutin interactions
will be discovered with further investigations.
INTRODUCTION
Rifampin is a potent inducer of the hepatic and intestinal cytochrome
P-450 (CYP) enzyme system and the P-glycoprotein (P-gp) transport system,
which results in numerous clinically significant drug interactions.1-4 Schuetz
et al5 found that rifampin intracellular concentrations
and, therefore, the extent by which rifampin was able to induce CYP3A was
strongly correlated with P-gp levels.
P-glycoprotein is a transmembrane protein that is a member of the adenosine
triphosphate–binding cassette family, a group of molecules that control
concentrations of endogenous and exogenous substances across cell membranes
by functioning as cellular efflux pumps.6 The
gene that encodes this protein is the multidrug resistance gene (MDR1). MDR1 expression manifested as P-gp
is widely distributed throughout the body, and is found at many sites that
are key to drug bioavailability and distribution, such as the intestinal lumen,
the liver, the kidney, and the blood-brain barrier.6
Interpatient and intrapatient variability in the expression of the gene product
of MDR1, P-gp, has a significant effect on the bioavailability
and site distribution of many drugs. Hoffmeyer et al7
discovered that patients with specific polymorphisms of MDR1 had significantly different levels of P-gp activity in the duodenum.
Moreover, the ability of rifampin to induce P-gp and thereby lower digoxin
levels (described later) was greatly governed by these polymorphisms of the MDR1 gene. This may partially explain the wide interpatient
variability in CYP3A induction by rifampin. The subject of P-gp as a mechanism
for drug interactions has been recently reviewed.6
As the number of new agents marketed increases, the potential for clinically
significant drug interactions heightens. Since the last review of this topic
in the ARCHIVES,4 several new interactions
involving rifampin have been reported. In addition, because of the importance
of rifabutin in treating tuberculosis in patients with the acquired immunodeficiency
syndrome (AIDS),8 interactions with this agent
are included.
A summary of previously reviewed rifampin interactions1-4
that are well documented and of major clinical significance is given in Table 1, while rifampin interactions that
may be clinically relevant but less well documented are listed in Table 2.
|
|
|
|
Table 1. Rifampin Drug Interactions of Major Clinical Significance*
|
|
|
|
|
|
|
Table 2. Rifampin Drug Interactions*
|
|
|
PSYCHOTROPIC AGENTS
Sertraline Hydrochloride
Sertraline is a commonly used selective serotonin reuptake inhibitor
that is thought to undergo extensive first-pass metabolism by the CYP3A4 isoenzyme.
Markowitz and DeVane9 described a 34-year-old
man receiving rifampin, 600 mg/d, as part of treatment for a staphylococcal
skin infection, concurrently with sertraline, 200 mg/d. After 7 days of rifampin
therapy, the patient reported feeling anxious and excessively worried. Subsequent
blood samples revealed that sertraline concentrations increased 3-fold (from
18 to 55 ng/mL) 1 week after discontinuation of rifampin, and the active metabolite
of sertraline was increased greater than 2-fold. The treatment of the patient
was later changed to another agent after symptoms were still present 1 week
after discontinuing rifampin. These researchers suggest the potential for
therapeutic failure or withdrawal symptoms if inducers of CYP3A4 are used
during sertraline therapy.
Nortriptyline Hydrochloride
Two prior case reports have documented a decrease in nortriptyline levels
when used concomitantly with rifampin.4 Although
nortriptyline is predominantly metabolized by CYP2D6, Venkatakrishnan et al10 found that CYP3A4 contributes to the hydroxylation
of nortriptyline. Cytochrome P-450 3A4 is characterized as having a low affinity
and a low capacity for nortriptyline metabolism. However, the authors suggest
that the contribution by CYP3A4 increases as nortriptyline concentrations
increase because of impaired CYP2D6 function (eg, poor metabolizers [PMs]
or patients treated with CYP2D6 inhibitors) or concomitant administration
with an inducer of the CYP3A4 isoenzyme.
Buspirone Hydrochloride
Buspirone, a common anxiolytic agent, undergoes extensive first-pass
metabolism via the CYP3A4 isoenzyme. Lamberg et al11
conducted a randomized, placebo-controlled, crossover study of the effects
of rifampin on buspirone pharmacokinetics. Ten healthy volunteers received
rifampin, 600 mg/d, for 5 days and buspirone, 30 mg, on day 6. During the
rifampin phase, the area under the concentration-time curve (AUC) of buspirone
decreased by 89.6%. The maximum concentration (Cmax) and half-life
decreased by 83.7% and 52.8%, respectively. No subjects in the rifampin arm
had measurable buspirone concentrations at 6, 8, or 10 hours after taking
the therapeutic agent. These results indicate an increase in presystemic and
systemic clearance of buspirone.
The same group of investigators12 studied
the effects of rifampin on the active piperazine metabolite of buspirone.
Using samples from their previous study,11
plasma concentrations of the piperazine metabolite were not significantly
affected by rifampin. Based on the results of these studies, concomitant administration
of buspirone with rifampin should be avoided because of the potential for
therapeutic failure.
Clozapine
Joos et al13 described a 33-year-old
schizophrenic patient who was stable while receiving clozapine, 400 mg/d,
for 2 years. After 3 weeks of treatment with rifampin, 600 mg/d, as
part of treatment for pulmonary tuberculosis, the patient began experiencing
increased restlessness and paranoid thoughts. Subsequent clozapine serum concentrations
were dramatically reduced by 600%. On discontinuation of rifampin, clozapine
serum concentrations increased to the therapeutic level within 3 days.
Zolpidem Tartrate
Zolpidem, a short-acting hypnotic agent, is predominantly metabolized
by CYP3A4. In a randomized, balanced, placebo-controlled, crossover study
by Villikka et al,14 8 volunteers were used
to examine the possible interaction between rifampin and zolpidem. Rifampin,
600 mg/d, was administered for 5 days, with zolpidem, 20 mg, given on day
6. Rifampin reduced the AUC and the Cmax of zolpidem by 73% and
58%, respectively, and the half-life was decreased from 2.5 to 1.6 hours.
The pharmacodynamic effects (drowsiness) of zolpidem were also reduced and
shortened during the rifampin phase. These findings suggest that this interaction
is likely to be clinically relevant.
Midazolam
Reports of the induction of midazolam metabolism by rifampin have already
been reviewed,4 and the results of a new study15 are consistent with the previous findings. When midazolam,
15 mg, was administered orally on days 1 and 4 after a 5-day course of rifampin,
600 mg/d, the AUC of midazolam was decreased by 97.7% and 86.8%, respectively,
and the Cmax was decreased by 94.6% and 79.8%, respectively. Concentrations
of the active metabolite were also reduced by 20% to 40% of the control during
the rifampin phase. The researchers also concluded that if switching from
inhibition (in this study, with itraconazole) to induction of CYP3A4 enzymes,
a 400-fold change in the pharmacokinetics of oral midazolam may be observed.
Using midazolam as a substrate during rifampin induction, Gorski et al16 found that intestinal CYP3A4 may be preferentially
altered by rifampin.
CARDIOVASCULAR DRUGS
Simvastatin
Simvastatin, a widely used agent for hypercholesterolemia, and its active
metabolite, simvastatin acid, are metabolized to inactive metabolites by CYP3A4.
Kyrklund et al17 enrolled 10 healthy patients
in a randomized, placebo-controlled, crossover study to examine the effects
of rifampin on the pharmacokinetics of simvastatin. After a 5-day course of
rifampin, 600 mg/d, simvastatin, 40 mg, was given on day 6. Rifampin reduced
the AUC of simvastatin and simvastatin acid by 87% and 93%, respectively.
The Cmax of both agents was decreased by 90% by rifampin. Based
on the results of this study, it is likely that concomitant use of rifampin
with simvastatin may significantly reduce the cholesterol-lowering effect
of simvastatin. The researchers postulate that rifampin may interact with
lovastatin and atorvastatin calcium because of their CYP3A4 activity, but
further investigation is warranted. According to the manufacturer of fluvastatin
sodium, rifampin reduces the AUC and Cmax of the agent by 51% and
59%, respectively.18
Digoxin
There have been previous reports1-2
of a digoxin-rifampin interaction that involved patients with renal failure
or a moderate decline in renal function. In patients with normal renal function,
digoxin is eliminated from the body almost entirely as unchanged drug. Nonrenal
clearance mechanisms of this interaction have not been clearly defined.
Greiner et al19 examined the role of
intestinal P-gp in the interaction of digoxin and rifampin in 8 healthy men
given a 2-week course of rifampin, 600 mg/d, and then digoxin, 1 mg, either
orally or intravenously (IV). After rifampin administration, the AUC and Cmax of oral digoxin decreased by 43% and 58%, respectively. The oral
bioavailability of digoxin decreased by 30.1% during rifampin therapy. Rifampin
also increased intestinal P-gp levels 3.5-fold. These results suggest that
P-gp regulates digoxin disposition, which can lead to altered drug concentrations.
Patients should be closely monitored for arrhythmia control and signs and
symptoms of heart failure during concurrent rifampin administration.
Propafenone Hydrochloride
While one previous case report3 suggested
a clinically important interaction between rifampin and propafenone, 2 recent
controlled trials verify the importance of this interaction. Dilger et al20 studied the consequences of rifampin treatment on
propafenone disposition in CYP2D6 extensive metabolizer (EM) and PM phenotypes.
Twelve volunteers (6 EMs and 6 PMs) ingested rifampin, 600 mg/d, for 9 days,
followed by a single IV infusion of unlabeled propafenone, 140 mg, and a single
dose of labeled oral propafenone, 300 mg. There were no significant differences
in the pharmacokinetics of IV propafenone before and after rifampin administration;
however, the bioavailability of oral propafenone decreased by 67% and 41%
in the EM and PM groups, respectively. The propafenone metabolism mediated
by CYP2D6 was not enhanced; however, clearance via CYP3A4/1A2 and glucuronidation
and sulfation were greatly increased by rifampin. These results indicate a
67% and 71% reduction in active propafenone concentrations in the EM and PM
groups, respectively. Such reductions in propafenone concentrations may cause
a loss of arrhythmia control.
The same group of researchers21 found
similar data when evaluating the effects of rifampin on the pharmacokinetics
and pharmacodynamics of propafenone in elderly persons. Bioavailability decreased
by 87% and 52% in the EMs and PMs, respectively, during rifampin induction.
They also found that during enzyme induction, maximum QRS prolongation decreased
significantly after oral propafenone therapy. Induction of gut wall metabolism
may play a major role because gastrointestinal extraction of propafenone increased
almost 4-fold during rifampin administration.
ANTIRETROVIRAL AGENTS
The 3 commercially available rifamycin derivatives have different CYP3A
induction potencies. In vitro data demonstrate that rifampin is the most potent,
followed by rifapentine and rifabutin.22 Initial
clinical evidence indicated that rifabutin has less propensity than rifampin
to cause an important induction of drug metabolism, and these reports have
been reviewed.23 Consequently, the drug interactions
between rifabutin and protease inhibitors (PIs) and nonnucleoside reverse
transcriptase inhibitors, drugs with narrow therapeutic ranges, are easier
to manage than those with rifampin.24-25
The PIs and the nonnucleoside reverse transcriptase inhibitors not only are
CYP3A substrates but are also inhibitors and inducers of this same isoform,
with the net result being either an increase or a decrease of the rifabutin
levels, frequently necessitating rifabutin and PI dosage adjustment.24 The extent and effect of the inhibition of rifabutin
metabolism by amprenavir were demonstrated in a recent study by Polk et al.26 When combined with amprenavir in healthy volunteers,
rifabutin given at the standard dose of 300 mg/d was associated with poor
tolerability and resulted in leukopenia in 7 of 11 subjects. This abnormally
high rate of adverse reactions could have been caused by the nearly 3-fold
increase in rifabutin's AUC. For this reason, the rifabutin dose must be decreased
and/or the dosing interval increased when coadministered with a PI.24 Spradling et al27
found that even after adjusting the rifabutin and antiretroviral agent doses,
rifabutin levels were suboptimal among many patients taking more than one
PI or PIs combined with efavirenz. However, Narita et al28
found that after rifabutin and PI doses were adjusted, rifabutin levels were
only marginally lower in patients receiving either indinavir or nelfinavir
mesylate based on highly active antiretroviral therapy (HAART), a reduction
that was not clinically significant. Among the nucleoside reverse transcriptase
inhibitors, a drug interaction between a nucleoside and rifamycin has only
been reported with zidovudine. Rifabutin and rifampin decreased the zidovudine
AUC by 32% and 47%, respectively.29-30
A dramatic reduction (25%-96%) in the AUC of PIs and nonnucleoside reverse
transcriptase inhibitors occurs when rifampin is coadministered because of
CYP3A/P-gp induction (Table 3).
The most recent Centers for Disease Control and Prevention guidelines state
that rifampin should only be administered in individuals undergoing HAART
in 3 situations: (1) if the patient is taking efavirenz, (2) if the patient
is taking ritonavir, or (3) if the patient is taking ritonavir plus saquinavir
mesylate. However, more recent evidence suggests that these guidelines may
require modification. While the ritonavir-saquinavir combination dosed at
400 mg each twice daily given with rifampin resulted in adequate levels of
saquinavir, newer methods of dosing this combination (ritonavir, 100 mg/d,
and saquinavir, 1600 mg/d; or ritonavir, 100 mg, and saquinavir, 1000 mg,
both twice daily) are being used, which may result in a different magnitude
of interaction with rifampin. Indeed, De Gast et al31
found that rifampin administered with 100 mg of ritonavir and 800 mg of indinavir,
twice daily, resulted in a greatly reduced indinavir AUC. In addition, the
most recent Centers for Disease Control and Prevention guidelines24 state that no dosage adjustment is necessary when
efavirenz is given with rifampin. However, efavirenz levels were significantly
lowered when given with rifampin at the usual efavirenz dose of 600 mg, but
were increased to the normal range when the efavirenz dose was increased to
800 mg, a strategy that proved successful in treating patients coinfected
with the human immunodeficiency virus (HIV) and tuberculosis.32-33
|
|
|
|
Table 3. Percentage by Which Rifampin and Rifabutin Lower the AUC of
PIs and NNRTIs*
|
|
|
ANTIBIOTICS COMMONLY USED AS TREATMENT OR PROPHYLAXIS OF OPPORTUNISTIC
INFECTIONS IN PATIENTS WITH HIV OR AIDS
Dapsone
In 7 HIV-positive patients receiving 100 mg of dapsone twice weekly
for Pneumocystis carinii pneumonia prophylaxis, rifampin
increased dapsone clearance by 69% to 122% (depending on which pharmacokinetic
models were used), a magnitude that would most likely be clinically significant.34 The investigators believed that the increased clearance
of dapsone was largely because of a significant first-pass effect. Moreover,
they observed that monoacetyldapsone was undetectable in plasma.
Azithromycin
Two different dosing regimens of azithromycin and rifabutin were evaluated
in HIV-positive and HIV-negative volunteers.35
Fifty study subjects received either 1200 mg of azithromycin plus 600 mg of
rifabutin daily or 600 mg of azithromycin plus 300 mg of rifabutin daily.
While no significant drug interactions were found between the 2 drugs, the
rate of neutropenia was quite high at 66%, as were the rates of gastrointestinal
adverse reactions. Whether these adverse reactions would occur to the same
degree with the standard dose of azithromycin, 1200 mg /wk, used for Mycobacterium avium-intracellulare complex prophylaxis
is not known. A study36 in healthy volunteers
given concomitant rifabutin and either azithromycin or clarithromycin also
revealed the risk of neutropenia, which occurred in all 12 subjects given
either agent with rifabutin.
Clarithromycin
The pharmacokinetics of clarithromycin, dosed at 500 mg twice daily,
plus rifabutin, dosed at 300 mg/d, were evaluated in 34 patients with HIV
or AIDS.37 A 44% reduction in the clarithromycin
AUC was observed, along with a 99% increase in the rifabutin AUC, when compared
with those values obtained in the same individuals while taking only one of
these drugs. Likewise, the metabolites 14-OH-clarithromycin and 25-O-desacetyl-rifabutin were increased by 57% and 357%, respectively.
While these mean values are significant, interpatient variability was high,
with some patients experiencing much larger (>150%) increases in the rifabutin
AUC. The researchers concluded that the elevated AUC of rifabutin that occurs
when given with clarithromycin is likely the cause of the increased incidence
of uveitis observed in patients receiving this combination therapy.
Fluconazole and/or Clarithromycin
Researchers38 found, in 10 HIV-infected
patients, that when rifabutin, 300 mg/d, was administered with either clarithromycin,
500 mg/d, or fluconazole, 200 mg/d, the rifabutin AUC was increased by 76%.
When clarithromycin and fluconazole were administered simultaneously with
rifabutin at the previously mentioned doses, the metabolic inhibitory effect
was additive, with a 152% increase in the rifabutin AUC. These authors caution
that in real clinical situations, many drugs are given concomitantly and the
extent of drug interactions is difficult to predict based on pharmacokinetic
studies only examining 2 drugs.
Itraconazole
Itraconazole and rifampin are commonly used together in HIV-infected
patients, and literature4 revealing an interaction
between these 2 agents has been reviewed. A new study has emerged to further
substantiate evidence of an interaction. Jaruratanasirikul and Sriwiriyajan39 studied 6 healthy patients and 3 patients with AIDS
to evaluate the effect of rifampin on the pharmacokinetics of itraconazole.
All subjects received rifampin, 600 mg, for 2 weeks followed by a single 200-mg
dose of oral itraconazole. On concomitant administration, itraconazole serum
concentrations were undetectable in all but one healthy volunteer, whose levels
were quite low. Based on these data, the concurrent use of rifampin and itraconazole
should be avoided because of the risk of therapeutic failure.
IMMUNOSUPPRESSANTS
Two case reports suggestive of clinically relevant interactions of rifampin
with tacrolimus (a substrate for CYP3A4 and P-gp) have been previously summarized.4 Hebert et al40 evaluated
the pharmacokinetics of tacrolimus in 6 healthy volunteers. Subjects were
treated with either a single oral dose (0.1 mg/kg) or an IV dose (0.025 mg/kg)
of tacrolimus, before and after 18 days of rifampin, 600 mg/d. With coadministration
of rifampin, the clearance of tacrolimus increased nearly 50%. Oral bioavailability
also decreased 50% during concomitant rifampin therapy. Chenhsu et al41 described a 61-year-old kidney transplant recipient
in whom tacrolimus therapy was maintained. Rifampin was prescribed as part
of tuberculosis therapy, and subsequent tacrolimus serum concentrations decreased
from 5 to 8 to 1.5 ng/mL. A 10-fold increase in the tacrolimus dose was needed
to maintain pre-rifampin serum concentrations. These results are consistent
with previous reports and warrant the need for careful monitoring of tacrolimus
trough concentrations when rifampin is added to either IV or oral tacrolimus
therapy.
Although the highly significant rifampin-cyclosporine interaction has
been previously reviewed,2 the effects of rifampin
on cyclosporine disposition continue to be evaluated.42
Kim et al43 found that doses of cyclosporine
had to be increased 2.5- to 3-fold to maintain satisfactory blood concentrations.
ANTIEMETIC AGENTS
Ondansetron Hydrochloride
A randomized crossover study44 in 10
healthy volunteers suggested that rifampin may cause a clinically significant
interaction with ondansetron, a potent antiemetic agent. Ondansetron, 8 mg
IV and orally, was administered before and after rifampin, 600 mg/d, for 5
days. The AUC of oral and IV ondansetron was reduced by 65% and 48%, respectively,
after rifampin administration. Rifampin decreased the Cmax of oral
ondansetron by 50% and increased IV ondansetron clearance by 83%. Based on
these results, concomitant use of rifampin with ondansetron may result in
a reduced antiemetic effect.
Dolasetron Mesylate
Dimmitt et al45 studied the pharmacokinetic
disposition of dolasetron, 200 mg, and its active metabolite, hydrodolasetron,
in 18 healthy men before and after the administration of rifampin, 600 mg/d,
for 1 week. Dolasetron plasma concentrations were below the detectable limit
throughout all phases of the study, but during concurrent rifampin treatment,
the clearance of hydrodolasetron increased by 39%. Although the researchers
suggested that no dosage adjustment is necessary during concomitant rifampin
administration, studies in patients are needed to verify that no dosage increases
will be required.
OPIATES
Fromm et al46 discussed a loss of the
analgesic effect of morphine sulfate in 10 healthy volunteers because of the
coadministration of rifampin. Morphine, 10 mg orally, was administered before
and near the end of 13 days of treatment with rifampin, 600 mg/d. Rifampin
therapy resulted in a significant reduction in the AUC (28%) and the Cmax (41%) of morphine. Using the cold pressor test to determine pain
sensation, the administration of rifampin resulted in no analgesic effect
of morphine. Because a major drug interaction was observed between morphine
and rifampin, the assessment of pain should be performed more frequently during
rifampin therapy to determine a loss of the analgesic effect. The need for
increased morphine doses should be anticipated.
Caraco et al47 evaluated the effects
of rifampin on codeine phosphate pharmacokinetics and pharmacodynamics in
15 healthy men (9 EMs and 6 PMs). Single-dose oral codeine, 120 mg, was administered
before and 3 weeks after rifampin therapy, 600 mg/d. The codeine plasma AUC
was decreased by a mean of 79% (in EMs) and 83% (in PMs). Codeine is metabolized
by O-demethylation (mediated by CYP2D6) to morphine
and N-demethylation to an inactive metabolite. While
rifampin induced O-demethylation only in EMs, it
increased N-demethylation to a greater degree (relative
to baseline values), with a resultant decrease in morphine concentrations.
Decreased morphine concentrations observed in EMs was associated with attenuation
of codeine's respiratory and psychomotor effects but not the miotic effect.
These pharmacodynamic changes did not occur in PMs. Because of reduced morphine
concentrations in EMs due to this interaction, some patients may have a diminished
analgesic effect.
A study48 was conducted evaluating the
ethnic variability in the effect of rifampin on codeine disposition and pharmacodynamics.
Codeine metabolism via O-demethylation to morphine
and N-demethylation to an inactive metabolite was
assessed. Caraco et al48 found that morphine's
AUC in Chinese volunteers was not altered during rifampin therapy, while there
was a significant decrease in the morphine AUC in white persons. Based on
these observations, rifampin's preferential induction of codeine to inactive
metabolite over morphine is ethnically dependent. Clinical significance is
still to be determined.
OTHER DRUGS
The antiestrogen agents, tamoxifen citrate and toremifene citrate, undergo
metabolism mediated by CYP3A4. Kivisto et al49
conducted 2 randomized, placebo-controlled, crossover studies to evaluate
the effects of rifampin on the pharmacokinetics of tamoxifen and toremifene
in 10 and 9 healthy volunteers, respectively. Volunteers took either 600 mg
of rifampin or placebo orally once a day for 5 days; on the sixth day, 80
mg of tamoxifen or 120 mg of toremifene was administered. Rifampin significantly
reduced the plasma concentrations of tamoxifen and toremifene, with the AUC
reduced by 86% and 87%, respectively. The Cmax and half-life of
both agents were also decreased by 55% and 44%, respectively, with rifampin
treatment. The pharmacokinetic variables of the active metabolites for each
agent changed significantly vs placebo during rifampin therapy. Although the
clinical significance of these interactions has yet to be determined, the
dosage of tamoxifen and toremifene may need significant adjustment during
concomitant use of rifampin.
The highly important rifampin–oral contraceptive interaction (induction
of estrogen and progesterone metabolism) has already been reviewed,1 and a new study50 evaluating
rifampin and rifabutin effects on oral contraception has been conducted. Although
the effects of rifampin were significantly greater than those of rifabutin,
an alternate form of birth control should be used, along with patient counseling
and documentation with either agent.
Nolan et al51 described a 50-year-old
man with a history of hypothyroidism who was stable while taking levothyroxine
sodium, 0.025 mg/d. Rifampin, 600 mg/d, was added as part of therapy for persistent
infection with methicillin sodium–resistant Staphylococcus
aureus. After 2 weeks of rifampin therapy, the patient's thyrotropin
level increased by 202% (9.44 mmol/L) from the most recent pretreatment thyrotropin
value (4.67 mmol/L). Thyrotropin levels returned to baseline 9 days after
discontinuation of rifampin therapy. The researchers suggested that this interaction
may be due to enhanced hepatic clearance of the levothyroxine.
Rifampin decreases the plasma concentrations and effects of repaglinide,52 an oral hypoglycemic agent extensively metabolized
by CYP3A4. Repaglinide, 0.5 mg, was administered to 9 healthy volunteers before
and after a 5-day course of rifampin, 600 mg/d. Concomitant treatment with
rifampin significantly decreased the mean AUC of repaglinide by 57% and the
Cmax by 41%. Subsequently, blood glucose concentrations were increased
significantly during rifampin administration. These researchers suggested
that blood glucose concentrations should be closely monitored and that the
repaglinide dosage should be adjusted appropriately during CYP3A4 induction.
This same group of investigators studied the effect of rifampin on the pharmacokinetics
and pharmacodynamics of glyburide and glipizide in 10 healthy subjects. Consistent
with initial case reports previouslyreviewed,3-4
these investigators found that rifampin, 600 mg/d orally for 5 days, significantly
affects glyburide plasma concentrations (decreased the AUC by 39%).53 The maximum decrease in blood glucose concentrations
due to this interaction was 36%. Rifampin decreased glipizide's AUC by 22%.53
Hamman et al54 studied the effects of
rifampin, 600 mg/d for 6 days, on the disposition of a single dose of fexofenadine
hydrochloride, 60 mg, in 24 healthy volunteers. After rifampin therapy, all
of the subjects had a significant increase in the oral clearance, with individual
increases ranging from 1.3- to 5.3-fold. There was also a significant reduction
in the peak serum concentration of fexofenadine. Because fexofenadine is eliminated
as unchanged drug, the researchers concluded that the increased clearance
and decreased concentrations are caused by an induction of intestinal P-gp.
The clinical relevance of this study has yet to be determined.
Djojosaputro et al55 evaluated the elimination
kinetics of IV metronidazole, 500 and 1000 mg, after pretreatment with rifampin,
450 mg/d for 7 days, in 10 healthy volunteers. Pretreatment with rifampin
increased the clearance of metronidazole by 44% and decreased the AUC by 33%
for both metronidazole doses.
Although most of the literature focuses on the effects of rifampin on
other drugs, some agents have effects on rifampin.4
In a study56 of 14 volunteers, antacid coadministration
had no effect on the absorption of rifampin; however, food significantly reduced
the Cmax by 36% and increased the time to peak concentration by
103%. These findings suggest that rifampin should be taken on an empty stomach
to avoid these kinetic changes.
CONCLUSIONS
Rifampin has numerous well-documented clinically significant drug interactions
associated with its use. Since the initial discovery of several important
rifampin interactions more than 25 years ago, new interactions continue to
be found. Updated information on rifampin interactions is summarized in Table 4. As rifabutin use continues to
increase in patients with HIV or AIDS, drug interactions with this agent are
increasingly being reported. Although rifabutin interactions are generally
less dramatic than rifampin interactions, many are clinically relevant. Table 3 offers a comparison of rifabutin
and rifampin interactions. Whenever clinicians prescribe therapy with either
rifampin or rifabutin, it is prudent to screen for drug interactions. As these
agents continue to be used, discovery of new interactions should be anticipated.
|
|
|
|
Table 4. Updated Rifampin Drug Interactions*
|
|
|
AUTHOR INFORMATION
Accepted for publication September 6, 2001.
Corresponding author and reprints: Timothy H. Self, PharmD, Department
of Clinical Pharmacy, University of Tennessee, 26 S Dunlap, Suite 210, Memphis,
TN 38163.
From the Department of Clinical Pharmacy, University of Tennessee,
Memphis (Drs Finch and Self); Secure Pharmacy, Franklin, Tenn (Dr Chrisman);
and Department of Pharmacy Services, University Hospitals of Cleveland, Cleveland,
Ohio (Dr Baciewicz). Dr Finch is now with the Department of Pharmacy Practice,
Auburn University, Auburn, Ala, and Dr Chrisman is now with the Department
of Pharmacy, Methodist Medical Center of Oak Ridge, Oak Ridge, Tenn. Dr Chrisman
has no type of investment of involvement with any pharmaceutical companies
via stock or mutual funds. He has consultant arrangements for which he receives
no compensation, financial or otherwise, with the following pharmaceutical
companies: Merck & Co, Inc, Whitehouse Station, NJ; Roche, Nutley, NJ;
Bristol-Myers Squibb, Wallingford, Conn; and Agouron Pharmaceuticals, Inc,
La Jolla, Calif. Dr Baciewicz owns drug company stocks (including stocks for
GlaxoSmithKline, Research Triangle Park, NC; Merck & Co, Inc; Pfizer Inc,
New York, NY; and Bristol-Myers Squibb) in addition to drug company stocks
via mutual funds. Dr Self receives standard speaking/consulting honoraria
from GlaxoSmithKline; Merck & Co, Inc; and other pharmaceutical companies
related to his expertise on asthma therapy. (These companies may have products
discussed in this review.) Dr Self has received investigator-initiated grants
from GlaxoSmithKline for asthma clinical investigations. He also owns stock
in several pharmaceutical companies, primarily via mutual funds.
REFERENCES
| |
1. Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med. 1984;144:1667-1671.
FULL TEXT
|
ISI
| PUBMED
2. Baciewicz AM, Self TH, Bekemeyer WB. Update on rifampin drug interactions. Arch Intern Med. 1987;147:565-568.
FREE FULL TEXT
3. Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions II. Arch Intern Med. 1992;152:711-716.
FREE FULL TEXT
4. Strayhorn VA, Baciewicz AM, Self TH. Update on rifampin drug interactions, III. Arch Intern Med. 1997;157:2453-2458.
FREE FULL TEXT
5. Schuetz EG, Schinkel AH, Relling MV, Schuetz JD. P-glycoprotein: a major determinant of rifampicin-inducible expression
of cytochrome P4503A in mice and humans. Proc Natl Acad Sci U S A. 1996;93:4001-4005.
FREE FULL TEXT
6. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today. 2001;6:835-839.
FULL TEXT
|
ISI
| PUBMED
7. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple
sequence variations and correlation of one allele with P-glycoprotein expression
and activity in vivo. Proc Natl Acad Sci U S A. 2000;97:3473-3478.
FREE FULL TEXT
8. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with
human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep. 1998;47:1-58.
PUBMED
9. Markowitz JS, DeVane CL. Rifampin-induced selective serotonin reuptake inhibitor withdrawal
syndrome in a patient treated with sertraline. J Clin Psychopharmacol. 2000;20:109-110.
FULL TEXT
|
ISI
| PUBMED
10. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6
(high affinity) and CYP3A4 (low affinity): implications for interactions with
enzyme-inducing drugs. J Clin Pharmacol. 1999;39:567-577.
ABSTRACT
11. Lamberg TS, Kivisto KT, Neuvonen PJ. Concentrations and effects of buspirone are considerably reduced by
rifampicin. Br J Clin Pharmacol. 1998;45:381-385.
FULL TEXT
|
ISI
| PUBMED
12. Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with itraconazole and rifampicin: effects
on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite
of buspirone. Pharmacol Toxicol. 1999;84:94-97.
ISI
| PUBMED
13. Joos AA, Frank UG, Kaschka WP. Pharmacokinetic interaction of clozapine and rifampicin in a forensic
patient with an atypical mycobacterial infection. J Clin Psychopharmacol. 1998;18:83-85.
FULL TEXT
|
ISI
| PUBMED
14. Villikka K, Kivisto KT, Luurila H, Neuvonen PJ. Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther. 1997;62:629-634.
FULL TEXT
|
ISI
| PUBMED
15. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam
is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol. 1998;54:53-58.
FULL TEXT
|
ISI
| PUBMED
16. Gorski JC, Craven R, Haehner-Daniels B, Clements JA, Bruce MA, Hall SD. The effect of rifampin on intestinal and hepatic CYP3A activity [abstract]. Clin Pharmacol Ther. 2000;67:133.
17. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 2000;68:592-597.
FULL TEXT
|
ISI
| PUBMED
18. Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am J Cardiol. 1994;73:18D-24D.
19. Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin
and rifampin. J Clin Invest. 1999;104:147-153.
ISI
| PUBMED
20. Dilger K, Greiner B, Fromm MF, Hofmann U, Kroemer HK, Eichelbaum M. Consequences of rifampicin treatment on propafenone disposition in
extensive and poor metabolizers of CYP2D6. Pharmacogenetics. 1999;9:551-559.
ISI
| PUBMED
21. Dilger K, Hofmann U, Ulrich K. Enzyme induction in the elderly: effect of rifampin on the pharmacokinetics
and pharmacodynamics of propafenone. Clin Pharmacol Ther. 2000;67:512-520.
FULL TEXT
|
ISI
| PUBMED
22. Li AP, Reith MK, Rasmussen A, et al. Primary human hepatocytes as a tool for the evaluation of structure-activity
relationship in cytochrome P450 induction potential of xenobiotics: evaluation
of rifampin, rifapentine, and rifabutin. Chem Biol Interact. 1997;107:17-30.
FULL TEXT
|
ISI
| PUBMED
23. Blaschke TF, Skinner MH. The clinical pharmacokinetics of rifabutin. Clin Infect Dis. 1996;22(suppl 1):S15-S22.
24. Centers for Disease Control and Prevention. Updated guidelines for the use of rifabutin or rifampin for the treatment
and prevention of tuberculosis among HIV-infected patients taking protease
inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep. 2000;49:185-189.
PUBMED
25. Guidelines for the Use of Antiretroviral Agents in HIV-Infected
Adults and Adolescents. Washington, DC, and San Francisco, Calif: Dept of Health and Human
Services and the Henry J Kaiser Family Foundation; 2001.
26. Polk RE, Brophy DF, Israel DS, et al. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin
in healthy males. Antimicrob Agents Chemother. 2001;45:502-508.
FREE FULL TEXT
27. Spradling P, McLaughlin S, Drociuk D, Ridzon R, Pozsik C, Onorato I. Concurrent use of rifabutin and HAART: evidence for reduced efficacy. Paper presented at: 13th International AIDS Conference; July 9-14,
2000; Durban, South Africa.
28. Narita M, Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutin with protease inhibitors for human immunodeficiency
virus–infected patients with tuberculosis. Clin Infect Dis. 2000;30:779-783.
FULL TEXT
|
ISI
| PUBMED
29. Mycobutin package insert. In: Physicians' Desk Reference. 53rd ed.
Montvale, NJ: Medical Economics Books; 1999:2501-2502.
30. Gallicano KD, Sahai J, Shula VK, et al. Induction of zidovudine glucuronidation and amination pathways by rifampicin
in HIV-infected patients. Br J Clin Pharmacol. 1999;48:168-179.
FULL TEXT
|
ISI
| PUBMED
31. De Gast M, Burger D, De Lange W, Van Crevel R. Double trouble: a pharmacokinetic study of indinavir/ritonavir (800
+ 100mg bid) and rifampin for patients co-infected with TB and HIV. Paper presented at: Second International Workshop on Clinical Pharmacology
of HIV Therapy; April 2-4, 2001; Noordwijk, the Netherlands.
32. Lopez-Cortex LF, Ruiz R, Viciana A, et al. Pharmacokinetic interactions between rifampin and efavirenz in patients
with tuberculosis and HIV infection. Paper presented at: Eighth Conference on Retroviruses and Opportunistic
Infections; February 4-8, 2001; Chicago, Ill.
33. Hung CC, Chen MY, Hsieh SM, Yang SJ, Lo PY, Chang SC. Efficacy of highly active antiretroviral therapy combined with rifamycin-containing
antituberculous therapy in HIV-1 infected patients with tuberculosis. Paper presented at: Eighth Conference on Retroviruses and Opportunistic
Infections; February 4-8, 2001; Chicago, Ill.
34. Gatti G, Merighi M, Hossein J, et al. Population pharmacokinetics of dapsone administered biweekly to human
immunodeficiency virus–infected patients. Antimicrob Agents Chemother. 1996;40:2743-2748.
ABSTRACT
35. Hafner R, Bethel J, Standiford HC. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother. 2001;45:1572-1577.
FREE FULL TEXT
36. Apseloff G, Foulds G, LaBoy-Goral L, Willavize S, Vincent J. Comparison of azithromycin and clarithromycin in the interactions with
rifabutin in healthy volunteers. J Clin Pharmacol. 1998;38:830-835.
ABSTRACT
37. Hafner R, Bethel J, Power M. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin
in human immunodeficiency virus–infected volunteers. Antimicrob Agents Chemother. 1998;42:631-639.
FREE FULL TEXT
38. Jordan MK, Polis MA, Kelly G, Narang PK, Masur H, Piscitelli SC. Effects of fluconazole and clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics. Antimicrob Agents Chemother. 2000;44:2170-2172.
FREE FULL TEXT
39. Jaruratanasirikul S, Sriwiriyajan S. Effect of rifampicin on the pharmacokinetics of itraconazole in normal
volunteers and AIDS patients. Eur J Clin Pharmacol. 1998;54:155-158.
FULL TEXT
|
ISI
| PUBMED
40. Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol. 1999;39:91-96.
ABSTRACT
41. Chenhsu R, Loong C, Chou M, Lin M, Yang W. Renal allograft dysfunction associated with rifampin-tacrolimus interaction. Ann Pharmacother. 2000;34:27-31.
ABSTRACT
42. Freitag VL, Skifton RD, Lake KD. Effect of short-term rifampin on stable cyclosporine concentrations. Ann Pharmacother. 1999;33:871-872.
FULL TEXT
|
ISI
| PUBMED
43. Kim YH, Yoon YR, Kim YW, Shin JG, Cha IJ. Effects of rifampin on cyclosporine disposition in kidney recipients
with tuberculosis. Transplant Proc. 1998;30:3570-3572.
FULL TEXT
|
ISI
| PUBMED
44. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous
ondansetron. Clin Pharmacol Ther. 1999;654:377-381.
45. Dimmitt DC, Cramer MB, Keung A, Arumughan T, Weir SJ. Pharmacokinetics of dolasetron with coadministration of cimetidine
or rifampin in healthy subjects. Cancer Chemother Pharmacol. 1999;43:126-132.
FULL TEXT
|
ISI
| PUBMED
46. Fromm MF, Eckhardt K, Li S, et al. Loss of analgesic effect of morphine due to coadministration of rifampin. Pain. 1997;72:261-267.
FULL TEXT
|
ISI
| PUBMED
47. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determinants of codeine induction by rifampin: the
impact on codeine's respiratory, psychomotor and miotic effects. J Pharmacol Exp Ther. 1997;281:330-336.
FREE FULL TEXT
48. Caraco Y, Sheller J, Wood AJJ. Ethnic variability in the effect of rifampin on codeine disposition
and pharmacodynamics [abstract]. Clin Pharmacol Ther. 2000;67:98.
49. Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ. Tamoxifen and toremifene concentrations in plasma are greatly decreased
by rifampin. Clin Pharmacol Ther. 1998;64:648-654.
FULL TEXT
|
ISI
| PUBMED
50. Barditch-Crovo P, Trapnell CB, Ette E, et al. The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics
of a combination oral contraceptive. Clin Pharmacol Ther. 1999;65:428-438.
FULL TEXT
|
ISI
| PUBMED
51. Nolan SR, Self TH, Norwood JM. Interaction between rifampin and levothyroxine. South Med J. 1999;92:529-531.
FULL TEXT
|
ISI
| PUBMED
52. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther. 2000;68:495-500.
FULL TEXT
|
ISI
| PUBMED
53. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Effects of rifampin on the pharmacokinetics and pharmacodynamics of
glyburide and glipizide. Clin Pharmacol Ther. 2001;69:400-406.
FULL TEXT
|
ISI
| PUBMED
54. Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001;69:114-121.
FULL TEXT
|
ISI
| PUBMED
55. Djojosaputro M, Mustofa S, Donatus IA, Santoso B. The effects of doses and pre-treatment with rifampicin on the elimination
kinetics of metronidazole [abstract]. Eur J Pharmacol. 1990;183:1870.
FULL TEXT
56. Peloquin CA, Namdar R, Singleton MD, Nix DE. Pharmacokinetics of rifampin under fasting conditions, with food, and
with antacids. Chest. 1999;115:12-18.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
Archives of Internal Medicine Reader's Choice: Continuing Medical Education
Arch Intern Med. 2002;162(9):1071-1072.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs
Sousa et al.
J Antimicrob Chemother 2008;62:872-878.
ABSTRACT
| FULL TEXT
A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine
Yasuda et al.
Drug Metab. Dispos. 2008;36:1689-1697.
ABSTRACT
| FULL TEXT
Addition of Rifampin to Standard Therapy for Treatment of Native Valve Infective Endocarditis Caused by Staphylococcus aureus
Riedel et al.
Antimicrob. Agents Chemother. 2008;52:2463-2467.
ABSTRACT
| FULL TEXT
Effect of Rifampin, an Inducer of CYP3A and P-glycoprotein, on the Pharmacokinetics of Risperidone
Kim et al.
J Clin Pharmacol 2008;48:66-72.
ABSTRACT
| FULL TEXT
Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model
Byrne et al.
J Med Microbiol 2007;56:1047-1051.
ABSTRACT
| FULL TEXT
Absence of Effect of Oral Rifaximin on the Pharmacokinetics of Ethinyl Estradiol/Norgestimate in Healthy Females
Trapnell et al.
The Annals of Pharmacotherapy 2007;41:222-228.
ABSTRACT
| FULL TEXT
Pharmacokinetic Study of Tenofovir Disoproxil Fumarate Combined with Rifampin in Healthy Volunteers
Droste et al.
Antimicrob. Agents Chemother. 2005;49:680-684.
ABSTRACT
| FULL TEXT
Interaction of Warfarin With Drugs, Natural Substances, and Foods
Greenblatt and von Moltke
J Clin Pharmacol 2005;45:127-132.
ABSTRACT
| FULL TEXT
CONVERSION OF THE HIV PROTEASE INHIBITOR NELFINAVIR TO A BIOACTIVE METABOLITE BY HUMAN LIVER CYP2C19
Hirani et al.
Drug Metab. Dispos. 2004;32:1462-1467.
ABSTRACT
| FULL TEXT
THE INVOLVEMENT OF CYP3A4 AND CYP2C9 IN THE METABOLISM OF 17{alpha}-ETHINYLESTRADIOL
Wang et al.
Drug Metab. Dispos. 2004;32:1209-1212.
ABSTRACT
| FULL TEXT
The Influence of St. John's Wort on CYP2C19 Activity with Respect to Genotype
Wang et al.
J Clin Pharmacol 2004;44:577-581.
ABSTRACT
| FULL TEXT
Concomitant Administration of Lumiracoxib and a Triphasic Oral Contraceptive Does Not Affect Contraceptive Activity or Pharmacokinetic Profile
Kalbag et al.
J Clin Pharmacol 2004;44:646-654.
ABSTRACT
| FULL TEXT
Inhibitors of Calcineurin
Holt et al.
Journal of Pharmacy Practice 2003;16:414-433.
ABSTRACT
Lack of Enzyme-Inducing Effect of Rifampicin on the Pharmacokinetics of Enfuvirtide
Boyd et al.
J Clin Pharmacol 2003;43:1382-1391.
ABSTRACT
| FULL TEXT
Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 During Rifampin Use
Bergshoeff et al.
The Annals of Pharmacotherapy 2003;37:521-525.
ABSTRACT
| FULL TEXT
|
