Journal of Clinical Pharmacy and Therapeutics (2007) 32, 161–167
ORIGINAL ARTICLE
Rifampin, a cytochrome P450 3A inducer, decreases
plasma concentrations of antipsychotic risperidone in
healthy volunteers
W. Mahatthanatrakul MD FRCFPT , T. Nontaput MSc , W. Ridtitid MD FRCFPT ,
M. Wongnawa MSc and M. Sunbhanich PhD
Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand
SUMMARY
Background: Although cytochrome P450 (CYP)
2D6 is often thought to be the only CYP respon-
sible for the metabolism of risperidone, many
reports suggest that CYP3A may be involved too.
Rifampin, a potent CYP3A inducer, has been
known to markedly decrease plasma concentra-
tions of various drugs, which are concomitantly
administered during treatment.
Objective: To examine the effect of rifampin on
plasma concentrations of a single oral dose of
risperidone in healthy Thai male volunteers.
Methods: In an open, randomized two-phase
crossover study, separated by a 2-week period, 10
healthy Thai male volunteers received a single
oral dose of 4-mg risperidone alone or with
600 mg rifampin, orally once daily for 5 days.
Serial blood samples were collected at specific
time points for a 48-h period. Risperidone was
measured in plasma using high performance
liquid chromatography with ultraviolet detection.
Pharmacokinetic parameters were determined by
using non-compartmental analysis.
Results: Co-administration with 600-mg rifampin
once daily for 5 days was associated with a sig-
nificant decrease in risperidone area under the
curve (AUC0--48) and maximal concentration (Cmax)
by 72% (157Æ49 ± 48Æ80 vs. 42Æ66 ± 7Æ81 ng/L/h;
P < 0Æ01) and 50% (32Æ44 ± 6Æ05 vs.
16Æ16 ± 2Æ73 ng/mL; P < 0Æ05), respectively when
compared with risperidone alone.
Received 3 January 2007, Accepted 30 January 2007
Correspondence: W. Ridtitid, MD, FRCFPT, Department of
Pharmacology, Faculty of Science, Prince of Songkla University,
Hat Yai 90112, Thailand. Tel/fax: +66 74 446678; e-mail:
wibool.r@psu.ac.th
 2007 The authors. Journal compilation  2007 Blackwell Publishing Ltd
Conclusions: Rifampin when used concurrently
with risperidone significantly decreases the
plasma concentration of risperidone. Our results
provide in vivo evidence of the involvement of
CYP3A in the metabolism of risperidone, in
addition to CYP2D6. Thus, co-administration of
risperidone with CYP3A inducer(s), including
rifampin should be recognized or avoided in
clinical practice.
Keywords: CYP3A inducer, drug–drug interac-
tions, pharmacokinetics, rifampin, risperidone
INTRODUCTION
Risperidone, an atypical antipsychotic drug, has
higher antagonist potencies at the serotonin 5-HT2A
receptors than dopamine D2 receptors or at almost
any other receptor (1). Clinical trials in psychotic
patients have shown that risperidone is effective
against both positive and negative symptoms in
the treatment of schizophrenia (2). Furthermore,
risperidone therapy at low doses produces fewer
extrapyramidal side-effects than usual doses of
conventional antipsychotic drugs (3). Because of
the favourable clinical effects of risperidone, its use
has increased substantially during the last few
years. Risperidone is rapidly and completely
absorbed after oral administration with <1%
excreted unchanged in the faeces (4). Risperidone is
extensively metabolized in the liver, primarily by
9-hydroxylation, resulting in 9-hydroxyrisperidone,
the principal active metabolite (5). Both in vivo and
in vitro data indicate that cytochrome P450 (CYP)
2D6 is involved in the 9-hydroxylation of risperi-
done (6, 7). Hydroxylation of risperidone is subject
to the same genetic CYP2D6-related polymorphism
161
162 W. Mahatthanatrakul et al.
as debrisoquine and dextromethorphan. The half-
life of risperidone is about 19 h in poor metabo-
lizers compared with about 3 h in extensive
metabolizers (4). The plasma concentrations of
risperidone, 9-hydroxyrisperidone, and risperi-
done plus 9-hydroxyrisperidone (active moiety) are
dose-proportional over the dosing range of
1–16 mg daily, with maximum antipsychotic activity
apparently occurring at doses of 4–8 mg daily (8).
Several in vitro studies have revealed that
CYP3A plays a minor role in the 9-hydroxylation of
risperidone (7). Interestingly, carbamazepine, an
inducer of CYP3A, reduces risperidone concentra-
tion in schizophrenic patients (9–11). Moreover,
there are many case reports, suggesting that drug
interactions are also involved with CYP3A in the
metabolism of risperidone (12–14). Recently, it has
been reported that itraconazole, a potent inhibitor
of CYP3A, has inhibitory effect on the metabolism
of risperidone, providing in vivo evidence of the
involvement of CY3A in the metabolism of
risperidone (15). Thus, all previous studies provide
strong evidence to suggest that CYP3A also plays
an important role in the metabolism of risperidone,
in addition to CYP2D6.
Rifampin is clinically used in the treatment of
tuberculosis, and therapy is usually administered
for 4–12 months together with other anti-tubercu-
losis drugs or other medication for an accom-
panying disease. Because rifampin is a potent
inducer of CYP3A4 and other CYP enzymes, it has
the potential for many drug interactions with con-
comitant drugs (16, 17). However, to our know-
ledge, there has been no report examining the effect
of rifampin, a potent CYP3A inducer, on the
pharmacokinetics of risperidone; hence this study.
METHODS
Subjects
Ten adult healthy Thai male volunteers were
recruited to this study. Each volunteer was given a
detailed explanation of the purpose, protocol and
risks of the study. They provided written
informed-consent to participate in this study which
was approved by the Ethics Committee, Faculty of
Medicine, Prince of Songkla University, Hat Yai,
Thailand. The mean age, body weight and body
mass index (± SD) of the 10 subjects were
 2007 The authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 161–167
30Æ5 ± 6Æ45 years, 55–76 kg and 22Æ09 ± 2Æ15 kg/m2,
respectively. All subjects were in good health on
the basis of medical history and physical exam-
ination. Routine blood tests including complete
differential blood counts, blood urea nitrogen,
creatinine, aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase, total
bilirubin, direct bilirubin, albumin, globulin and
fasting blood glucose were screened to exclude
abnormal haematological, liver or kidney func-
tions. None of the volunteers smoked or used any
medication continuously. Subject with known
contraindication or hypersensitivity to antipsy-
chotic agent were excluded as were those with
known history of alcoholism or drug abuse.
Drinking of alcoholic beverages, coffee and tea
were not allowed for at least 1 month prior to and
during the entire period of study.
Study protocol
The study was used an open-labelled, randomized
two-phase crossover design with a 2-week wash
out period.
Treatment A: risperidone alone. In the morning after
an overnight fast, each subject received a single
oral dose of 4-mg risperidone (two tablets of 2 mg
Risperdal; Dietheim Ltd for Janssen-Cilag, Bang-
kok, Thailand). The drug was administered with a
glass of water (200 mL) under supervision. No
food was taken at least 3 h after ingestion of the
drug. In the study day, a catheter was inserted into
a forearm vein for collection of blood samples, and
was maintained patent using 1 mL of a dilute
heparin solution (100 unit/mL) after each sample.
Venous blood samples (5 mL) were collected
in heparinized tubes immediately before drug
administration, and at 10, 20, 30, 45 min, 1, 1Æ5, 2, 4,
6, 8, 12, 24 and 48-h post-drug administration.
Samples were centrifuged not later than 30 min
after collection, and the plasma was separated and
stored at )70 C until analysis.
Treatment B: risperidone after rifampin. After 2 weeks
free from the drug, the subjects received rifampin
capsules at an oral dose of 600 mg (two capsules of
300 mg rifampin capsules) once daily after break-
fast for 5 days prior to a single oral dose of 4-mg
risperidone. On day 6 (after rifampin pretreatment

for 5 days), after an overnight fast, all subjects
received risperidone 4-mg orally. Venous blood
samples were collected at specific time intervals
before and after risperidone administration as
previously described for treatment A.
Sample analysis
The plasma risperidone concentrations were
measured by a high performance liquid chroma-
tographic (HPLC) method (18). Briefly, 20 lL of
clozapine (1 lg/mL), as internal standard, and
1 mL NaOH (2 M) were added to 1 mL of stored
plasma sample. The tubes were vortex-mixed for
10 s and 4 mL of di-isopropyl ether-isoamylalcohol
(99 : 1, vol/vol) was added as extraction solvent.
After shaking for 10 min, the mixture was centri-
fuged at 3000 g for another 10 min at 4 C and the
organic phase (upper phase) was transferred to
tubes containing 150 lL of KH2PO4 (0Æ1 M, pH 2Æ2
with 25% H3PO4), mixed for 1 min, and centri-
fuged at 3000 g for 5 min. The upper organic layer
was carefully aspirated and 1 mL of diethyl
ether was added. After gentle mixing, the ether
phase was eliminated and a 60 lL aliquot of the
remaining acid solution was injected onto an HPLC
system which consisted of a Waters 2695 pump, an
autosampler (Water Associates, Milford, MA, USA)
and a Waters 2487 ultraviolet (UV) detector. The
mobile phase was composed of 0Æ05 M potassium
dihydrogenphosphate and acetonitrile (68 : 32 vol/
vol), adjusted to pH 3Æ80 with 25% phosphoric
acid. Detection was performed with the variable-
wavelength UV detector set at 278 nm. The column
was reverse-phase Symmetry C18 (4Æ6 mm ·
250 mm HPLC column, particle size 5 lm, Waters
associates). A linear calibration curve of risperi-
done in the range of 2–100 ng/mL was performed
(r2 = 0Æ999). The lower limit of quantification (LOQ)
of risperidone was 2 ng/mL. The intraday coeffi-
cient of variation of risperidone was 4Æ46–10Æ54%,
whereas the interday coefficient of variation
was 4Æ12–13Æ94%. The relative recovery of
standard risperidone in human plasma was
98Æ72–109Æ52%.
Pharmacokinetic and statistical analysis
The pharmacokinetic parameters were analysed
using a non-compartment model and the software
 2007 The authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 161–167
Rifampin, a cytochrome P450 3A inducer 163
WinNonlin version 4Æ1 (Pharsight Corporation,
Mountain View, CA, USA). All results were
expressed as mean ± standard error of the mean
(SE). Differences in risperidone pharmacokinetic
parameters (AUC00)48, Cmax, t1/2, and Tmax)
between treatment A and B were tested by Wilc-
oxon signed-rank test with P-value <0Æ05 taken as
significant. A ANOVA was carried out on the phar-
macokinetic parameters AUC00)48 and Cmax using a
general linear model in which the main effects
(sequence, treatment and period) and the interac-
tion between subject and sequence were evaluated
(Table 3). No significant period or sequence effect
was observed in this study.
RESULTS
Adverse effects
The 10 adult healthy Thai male volunteers com-
pleted in this study. No serious side effects were
observed after taking 600 mg of rifampin. With
the single oral dose of risperidone, in both
treatments A and B, sleepiness, lasting 1–2 h, was
observed in all subjects. Only two subjects
reported dizziness, nasal congestion and mild
headache while three subjects had orthostatic
dizziness. All symptoms subsided within 1 day
and did not require any specific treatment.
Moreover, all subjects tolerated well all the drugs
used in the study. No marked laboratory abnor-
mality occurred in any subjects, and physical
examinations revealed no abnormal finding at the
end of the study.
Pharmacokinetic studies
The individual and mean pharmacokinetic
parameters of risperidone given alone and after
rifampin in the 10 adult healthy Thai male volun-
teers are summarized in Table 1 and Table 2,
respectively. The corresponding mean plasma
concentration–time profiles of risperidone alone
and after rifampin are shown in Fig. 1. After pre-
treatment with rifampin 600-mg orally once daily,
the mean values for AUC0)48, and Cmax were sig-
nificantly decreased by 73% (157Æ49 ± 48Æ80 vs.
42Æ66 ± 7Æ81 ng/L/h; P < 0Æ01) and 50%
(32Æ44 ± 6Æ05 vs. 16Æ16 ± 2Æ73 ng/mL; P < 0Æ05),
respectively when compared with risperidone
164 W. Mahatthanatrakul et al.

Table 1. Individual pharmacokinetic parameters of risperidone after receiving a single dose of risperidone 4-mg alone
(treatment A) and risperidone after rifampin (treatment B) in 10 healthy Thai male volunteers

Risperidone alone (treatment A) Risperidone after rifampin (treatment B)

AUC0)48 Cmax t1/2 Tmax AUC0)48 Cmax t1/2 Tmax

Subject (ng/L/h) (ng/mL) (h) (h) (ng/L/h) (ng/mL) (h) (h)

1 187Æ80 43Æ96 2Æ95 1 60Æ55 21Æ78 3Æ15 0Æ75

2 40Æ09 5Æ64 1Æ41 1 1Æ19 2Æ35 0Æ46 0Æ75
3 131Æ00 49Æ62 2Æ22 1 57Æ56 22Æ58 2Æ17 0Æ75
4 144Æ66 28Æ51 4Æ84 1 63Æ85 23Æ22 2Æ53 1
5 18Æ57 16Æ78 1Æ55 0Æ5 25Æ18 9Æ04 1Æ91 0Æ75
6 41Æ64 16Æ83 2Æ63 0Æ5 19Æ36 10Æ49 2Æ85 075
7 67Æ22 9Æ50 3Æ67 2 22Æ15 9Æ46 3Æ46 1
8 212Æ94 56Æ78 2Æ74 1 36Æ95 19Æ55 2Æ09 0Æ75
9 550Æ32 44Æ77 16Æ00 1 68Æ76 12Æ61 3Æ67 1Æ5
10 180Æ64 51Æ99 2Æ19 0Æ5 71Æ06 30Æ53 1Æ67 0Æ75
Mean 157Æ49 32Æ44 4Æ02 0Æ95 42Æ66 16Æ16 2Æ39 0Æ88
SE 48Æ80 6Æ05 1Æ36 0Æ13 7Æ81 2Æ73 0Æ30 0Æ07

Table 2. Pharmacokinetic parameters of risperidone in DISCUSSION

10 adult healthy Thai male volunteers following a single
oral dose of risperidone 4-mg alone or after administra- Results of this study revealed that rifampin was a
tion of rifampin 600-mg orally once daily for 5 days potent inducer of CYP3A. It significantly decreased
the mean AUC0)48 and Cmax of risperidone, indi-
Risperidone Risperidone after cating that it induced the metabolism of risperi-
alone rifampin done. There were no statistically significant
Parameters (treatment A) (treatment B) differences in t1/2 and Tmax between the two
treatments. A smaller AUC0)48 and lower Cmax of
AUC0)48 (ng/L/h) 157Æ49 ± 48Æ80 42Æ66 ± 7Æ81*
risperidone after pretreatment with rifampin is
% decrease 73
likely because of enhanced presystemic elimination
t1/2 (h) 4Æ02 ± 1Æ36 2Æ39 ± 0Æ30
% decrease 41 of risperidone. Risperidone AUC0)48, Cmax, t1/2 and
Tmax (h) 0Æ95 ± 0Æ13 0Æ88 ± 0Æ07 Tmax showed wide intersubject variability both
% decrease 7 with risperidone alone (treatment A) and with
Cmax (ng/mL) 32Æ44 ± 6Æ05 16Æ16 ± 2Æ73* pretreatment with rifampin (treatment B) (Table 1).
% decrease 50 The interindividual variability may be due to age-,
sex-, race- and other genetic-related effects (19).
Values are given as mean ± SE. Similar large interindividual variability has been
AUC, area under the plasma concentration-time curve; t1/2,
reported for the inductive effect of rifampin on
elimination half-life; Tmax, time to reach Cmax; Cmax,, maximum
plasma concentration.
triazolam metabolism in healthy volunteers (20).
* P < 0Æ01 significantly different compared with control phase Such variability has also been reported for risperi-
(Wilcoxon signed-rank test). done pharmacokinetics when the drug was
administered on its own (21). Rifampin is a potent
inducer of CYP3A4 not only in the liver but also in
alone. The t1/2 of risperidone was decreased by the intestine (22), and several studies have shown
41% (4Æ02 ± 1Æ36 vs. 2Æ39 ± 0Æ30; P > 0Æ05) by drug interaction between rifampin and other drugs
rifampin but this difference was not statistically (17, 20, 23–25). Our results have suggested that
significant. The Tmax value of risperidone was not rifampin enhanced the metabolism of risperidone
significantly changed with rifampin pretreatment during both presystemic and elimination phases
(0Æ95 ± 0Æ13 vs. 0Æ88 ± 0Æ07; P > 0Æ05). (decreased Cmax and shorter t1/2 values for

 2007 The authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 161–167
 Rifampin, a cytochrome P450 3A inducer 165

Table 3. ANOVA analysis of logarithmically transformed fected by rifampin. Therefore, the in vivo data in the
AUC0)48 and Cmax of treatment A and B in 10 healthy present investigation provides evidence for the
Thai male volunteers involvement of CYP3A in the metabolism of
risperidone.
Type III
It is well established that CYP2D6 plays an
sum of Mean
important role in the metabolism of risperidone (6, 7).
Source squares d.f. square F P
The 9-hydroxylation of risperidone, the major
AUC0)48 metabolic pathway, is dependent mainly on
Period 0Æ434 12 29Æ128 55Æ711 0Æ389 CYP2D6 activity (6, 7). The metabolite 9-hydroxy-
Sequence 0Æ858 1 0Æ858 1Æ641 0Æ236 risperidone is pharmacologically active (6). Some
Treatment 7Æ970 1 7Æ970 15Æ243 0Æ005 data suggest that CYP3A participates in the meta-
Subject·sequence 17Æ227 8 2Æ153 4Æ119 0Æ031 bolism of risperidone, in addition to CYP2D6 (7, 11,
Error 4Æ183 8 0Æ523 26). Recently, it has been reported that ketoconaz-
Total 353Æ721 20 ole, a potent inhibitor of CYP3A4, enhances plasma
Cmax concentrations of the anti-malarial mefloquine
Period 0Æ003 1 0Æ003 0Æ032 0Æ862
considerably in healthy volunteers by inhibition of
Sequence 0Æ061 1 0Æ061 0Æ764 0Æ407
CYP3A4-mediated metabolism (27). Itraconazole, a
Treatment 2Æ133 1 2Æ133 26Æ616 0Æ001
potent inhibitor of CYP3A, significantly increased
Subject·sequence 10Æ113 8 1Æ264 15Æ773 0Æ000
Error 0Æ641 8 0Æ080 the mean steady-state plasma concentration of ris-
Total 183Æ344 20 peridone and 9-hydroxyrisperidone in schizo-
phrenic patients by inhibiting the metabolism of
risperidone, providing in vivo evidence of the
involvement of CYP3A in the metabolism of the
Plasma risperidone concentration (ng/mL)

40
30
20
10
0
0 4
Fig. 1. Mean plasma risperidone concentration
(mean ± SE) in 10 adult healthy Thai male volunteers
after a single oral dose of 4-mg risperidone alone
(d: Treatment A) and after pretreatment with 600-mg
rifampin once daily for 5 days ( : Treatment B).
risperidone in treatment B). The liver and intestine
play an important role in the presystemic metabo-
lism of many CYP3A4 substrates, and rifampin is a
potent inducer of CYP3A4 in both these organs.
The decrease in plasma concentrations of risperi-
done after rifampin treatment is probably because
of enhanced metabolism in the liver rather than in
the gut wall, as the Tmax of risperidone was unaf-
latter (15). Similarly, other CYP3A4 inhibitors such
as ritonavir, indinavir and nefazodone interacted
with risperidone (26, 28, 29). Co-administration
with risperidone with carbamazepine, an inducer
Risperidone alone of CYP3A, reduced plasma concentrations of both
Risperidone after rifampin risperidone and 9-hydroxyrisperidone (9–11, 30).
Taking all these data together, the crucial role of
CYP3A in the metabolism of risperidone cannot be
excluded. However, the possibility of P-glycopro-
tein (P-gp) involvent in the disposition of risperi-
done in humans should be considered and further
8 12 16 20 24 28 32 36 40 44 48
Time (h) investigated. It has been estblished that P-gp is an
efflux pump in many epithelial cells with excretory
function. Several psychotropic drugs, including
risperidone, is a substrate of P-gp whereas it has
been indicated that rifampin induces P-gp, parti-
cularly in the gut wall. Therefore, rifampin would
induce P-gp-mediated excretion of risperidone
predominantly in the gut wall to decrease plasma
concentrations of risperidone, in addition to CYP
3A-mediated metabolism.
The therapeutic range of the active moiety,
9-hydroxyrisperidone, is narrow (20–60 ng/mL)
(31, 32). Therefore, CYP3A inducer(s), including
rifampin, may reduce plasma concentration of both
risperidone and 9-hydroxyrisperidone, leading to
the treatment failure in schizophrenic patients.

 2007 The authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 161–167
166 W. Mahatthanatrakul et al.
Thus, clinicians should be aware of this potential
interaction.
CONCLUSION
This study shows that 5-day pretreatment with
600 mg of oral rifampin causes a significant
reduction in plasma concentration of risperidone
by enhancing its metabolism in the liver rather than
the small intestine. The role of CYP2D6 in the
metabolism of risperidone is well known. This
study provided further evidence that CYP3A is
most likely also involved.
ACKNOWLEDGEMENTS
This study was supported by grants from the Fac-
ulty of Science and Graduate Studies, Prince of
Songkla University, Thailand. Thanks are also
given to nurses from Faculty of Medicine, Prince of
Songkla University for collection of blood samples.
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