Repeated Ingestion of Grapefruit Juice Does Not Alter Clozapine's Steady-State Plasma Levels, Effectiveness, and Tolerability
J Clin Psychiatry 2001;62:812-817
© Copyright 2014 Physicians Postgraduate Press, Inc.
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Background: Grapefruit juice can inhibit the
gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its
effect on CYP1A2 remains controversial. Several grapefruit juice
bioflavonoids also modulate the activity of the drug transporter
P-glycoprotein in the gut and in the blood-brain barrier. Both
CYP1A2 and CYP3A4 are involved in clozapine metabolism. This
study investigated the effects of repeated ingestion of
grapefruit juice on multiple-dose pharmacokinetics and
pharmacodynamics of clozapine in schizophrenic patients.
Method: Clozapine therapy was initiated for
fifteen treatment-resistant schizophrenic inpatients (DSM-IV
criteria). The doses were individually titrated from day -35 to
day -15 and then kept unchanged from day -14 to day 49.
Regular-strength grapefruit juice (250 mL) was coadministered
b.i.d. with each clozapine dose from day 15 to day 28. Plasma
levels of clozapine and its main metabolites (norclozapine and
clozapine N-oxide) were obtained, and clinical efficacy
and safety assessments were completed prior to juice
administration (days 0, 7, and 14), during the coadministration
(days 17, 21, and 28), and after cessation of the juice (days 35,
42, and 49).
Results: After reaching steady states, plasma
concentrations of clozapine and its metabolites and Positive and
Negative Syndrome Scale scores were not significantly altered by
the effect of grapefruit juice ingestion. The Clinical Global
Impressions scale scores, Calgary Depression Scale scores, and
side effect profiles (by the Extrapyramidal Symptom Rating Scale,
the UKU Side Effect Rating Scale, and thorough examinations
including electrocardiography and electroencephalography) also
remained constant during the study.
Conclusion: Consumption of regular-strength
grapefruit juice, 250 mL b.i.d., for 14 days did not
significantly impact clozapine metabolism, clinical efficacy, or
tolerability. One reason is that enzymes other than CYP3A4 also
mediate clozapine disposition. Also, grapefruit juice inhibits
CYP3A4 in the gut, but not in the liver. The preliminary results
also suggest that clozapine is unlikely to be a P-glycoprotein
substrate. Further rigorous studies are necessary to reconfirm