Omeprazole Reduces Clozapine Plasma Concentrations

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Omeprazole Reduces Clozapine We report on two patients who received omeprazole in addition to clozapine because of gastrointestinal complaints. The combi- Plasma Concentrations nation treatment with both omeprazole and clozapine was asso- A Case Report ciated with a reduction in the plasma levels of clozapine.

A. Frick1, J. Kopitz2, N. Bergemann1 Blood Specimens and Laboratory Analysis

Blood specimens were taken between 8 and 9 a.m., i.e., 10±12 h A number of interactions of the atypical antipsychotic clozapine after the last oral dose of clozapine in steady state. After solid- with other drugs are well known, some of which can be attributed phase extraction on C18 reversed-phase cartridges (Bond-Elut- in part to the pharmacokinetic interactions associated with cyto- C18; Varian, Harbor City, CA), isocratic high-performance liquid chrome P450enzymes during drug metabolism. Clozapine is chromatography (HPLC) analysis (HD2±400 pump, Besta, Wil-

mainly metabolized by the cytochrome P450isoenzyme 1A2. The helmsfeld, Germany) was performed on a 5 mm Hypersil C18 col- Letter proton pump inhibitor omeprazole can induce CYP1A2. We report umn (Ziemer Chromatographie, Mannheim, Germany) with UV on two patients with schizoaffective disorder who received ome- detection at 254 nm (UV/VIS detector 785 A, Applied Biosystems, prazole in addition to clozapine because of gastrointestinal com- Foster City, CA). The HPLC eluent consisted of acetonitril/water plaints. Before the co-medication with omeprazole was started, (40:60, v/v) containing 0.4% triethylamine and was adjusted to the patients had been receiving clozapine for 78 and 41 days and ph 6.5 with phosphoric acid. Imipramine was used as internal for 40and 8 days at a stable daily dose of 325 mg (patients 1 and 2, standard [17]. Mean recovery rate tested for 500 ng/ml was respectively). The co-medication with omeprazole was associated 82%. Day-to-day variations calculated from samples spiked with with a reduction in the plasma levels of clozapine of 41.9% and clozapine (100±1000 ng/ml) were 2.1±5.8%. The detection limit 44.7%, respectively, in these patients. The decrease in the plasma was 10ng/ml, and linear detector responses of up to 2000ng/ml concentrations of clozapine in the presence of omeprazole might with correlation coefficients of 0.990 0.001 were observed, as be due to the induction of the cytochrome P450isoenzyme calculated by linear regression analysis. CYP1A2. If patients are receiving omeprazole as co-medication, close monitoring of plasma clozapine levels is recommended. If clozapine levels drop, the drug should be adjusted accordingly. If Case Report: Patient 1 necessary, an alternative to omeprazole should be chosen. A 22-year-old man, who smoked on average 20cigarettes per day, was admitted to the hospital with a diagnosis of schizoaffec- Introduction tive disorder. To treat an antrum gastritis which was diagnosed by gastroscopy, he was given omeprazole (40mg/d). Before the 121 The atypical antipsychotic clozapine is a highly efficacious com- co-medication with omeprazole was administered, he had been pound that however, has a few well-known side effects. Further- receiving clozapine for 78 days, for 40days at a stable daily more, a number of interactions of clozapine with other drugs, dose of 325 mg. The clozapine plasma concentration was meas- especially with other psychotropics, are known, some of which ured 8 (t1) and 2 days before (t2) and 5 days after (t3) the begin- can be attributed in part to the pharmacokinetic interactions ning of the omeprazole treatment, which was continued at the associated with cytochrome P450enzymes during drug metab- same dose for the entire observation period. Between t2 and t3, olism [3]. Clozapine is metabolized by the cytochrome P450iso- the clozapine plasma concentration dropped from 762 ng/ml to enzymes CYP1A2 and CYP3A4 [4]. Although CYP2D6 and 443 ng/ml. Seven and 14 days thereafter (t4 and t5), the cloza- CYP2C19 are involved in clozapine metabolism [5,9], it is also pine plasma concentration still was reduced (510ng/ml and 385 known that inhibition of CYP1A2 elevates the plasma levels of ng/ml, respectively). Throughout the entire period, he also re- clozapine. ceived citalopram at unchanged dose (Fig.1).

The acid pump inhibitor omeprazole can induce cytochrome P4501A2 but shows no effects on CYP3A4 [1]. Case Report: Patient 2

A 31-year-old woman, who smoked on average 15 cigarettes per day, was admitted to the hospital with a diagnosis of schizoaffective disorder. She was taking omeprazole (60mg/d) to treat a re- Affiliation: 1 Department of Psychiatry, University of Heidelberg, Ger- flux esophagitis which had been diagnosed by gastroscopy. Be- many ´ 2 Institute of Pathochemistry and General Neurochemistry, University fore the co-medication with omeprazole started, she had already of Heidelberg, Germany been receiving clozapine for 41 days, for 8 days at a stable daily Correspondence: Dr. med. Dipl.-Psych. Niels Bergemann ´ Department of Psy- chiatry ´ Ruprecht-Karls-University of Heidelberg ´ Voss-Str. 4 ´ 69115 Heidel- dose of 325 mg. The clozapine concentration was measured 1 berg ´ Germany ´ Phone: +49 (0)6221/56-5411 ´ Fax: +49 (0)6221/56-5477 ´ E- day before (t1) and 7 days after (t2) the initiation of omeprazole mail: [email protected] treatment, which was continued during the whole observation Received 19.12.2001 ´ Revised 31.5.2002 ´ Accepted 1.7.2002 period at a daily dose of 60mg. Seven days after starting co-med- Bibliography: Pharmacopsychiatry 2003; 36: 121±123 ´ Georg Thieme Verlag ication with omeprazole, the plasma concentration had dropped Stuttgart ´ New York ´ ISSN 0176-3679 from 369 ng/ml to 204 ng/ml. Seven days thereafter (t3), the clo- low and in case 2 a high dose of omeprazole did not produce predictable effects.

The multidrug transporter p-glycoprotein appears to play a significant role in drug absorption, especially for those compounds with potential targets in the central nervous system [2]. Since omeprazole is a p-glycoprotein substrate [11], this might be a further explanation for the observed omeprazole/clozapine interaction. Whether clozapine is indeed a p-glycoprotein substrate remains to be elucidated. However, preliminary results suggest that this is unlikely [8].

A decrease in the clozapine plasma level of more than 40% has to

Letter be regarded as substantial. In a recent study, it could be demonstrated that a decrease in the clozapine plasma level of more Fig. 1 Clozapine plasma concentration curves before and after the in- than 40% of the initial plasma concentration under which the re- itiation of omeprazole medication in bothpatients; theolanzapine dai- mission occurs leads to a significant increase in the risk of re- ly dose amounted to 325 mg in each. lapse [7]. Clozapine levels of patients receiving omeprazole as co-medication should be closely monitored in order to recognize any plasma level reduction [16]. zapine plasma concentration was still reduced (207 ng/ml). Throughout the entire observation period, she was also taking li- If clozapine levels drop, the drug dose should be adjusted accord- thium and dibenzepine at unchanged doses (Fig.1). ingly. Furthermore, an acid pump inhibitor that does not interact with clozapine metabolizing cytochrome P450isoforms might be chosen. New proton pump inhibitors, such as rabeprazole, esome- Results prazole, or pantoprazole, may overcome the limitations of omeprazole and related compounds [13], but their lack of interference In both patients the combination treatment with omeprazole with clozapine metabolism remains to be demonstrated. and clozapine was associated with a reduction in the clozapine plasma levels of 41.9% and 44.7%, respectively. These reductions in the plasma levels of clozapine in both patients were not asso- References ciated with changes in clinical presentation, however. 1 122 Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Clin Pharmacokinet 1996; 31: 9±28 2 Ayrton A, Morgan P. Role of transport proteins in drug absorption, dis- Discussion tribution and excretion. Xenobiotica 2001; 31: 469 ±497 3 Edge SC, Markowitz JS, Devane CL. Clozapine drug interactions: a re- Omeprazole has been investigated in several studies with re- view of the literature. Human Psychopharmacol 1997; 12: 5±20 4 spect to its influence on the activity of CYP1A2 [1]. Except in Eiermann B, Engel G, Johansson I, Zanger UM, Bertilsson L. The invol- vement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J one of these studies [15], concentration-dependent inhibition of Clin Pharmacol 1997; 44: 439 ±446 CYP1A2 activity was not revealed; however, in the latter study 5 Fischer V, Vogels B, Maurer G, Tynes R. The antipsychotic clozapine is this effect was weak and without clinical relevance. An induction metabolized by the polymorphic human microsomal and recombi- of CYP1A2 by omeprazole has been demonstrated in poor and ex- nant cyochrome P4502D6. J Pharmacol Exp Ther 1992; 260:1355± 1366 tensive metabolizers [14]. 6 Flockhard DA. Drug interactions and the cytochrome P450system. The role of P4502C19. Clin Pharmacokinet 1995; 29: 45±52 Omeprazole, like lansoprazole, is a mixed inducer of CYP1A2 7 Gaertner I, Gaertner HJ, Vonthein R, Dietz K. Therapeutic drug moni- and CYP3A4 in human hepatocytes [10]. The cytochrome P450 toring of clozapine in relapse prevention: a five-year prospective study. J Clin Psychopharmacol 2001; 21: 305 ±310 isoforms 1A2, 2C19, and 3A4 are also major contributors to clo- 8 Lane HY, Jann MW, Chang YC, Chiu CC, Huang MC, Lee SH, Chang WH. zapine metabolism. In vitro studies have suggested that Repeated ingestion of grapefruit juice does not alter clozapine's stea- CYP1A2 is the most important form at low concentrations, dy state plasma levels. J Clin Psychiatry 2001; 62: 812±817 9 which is in agreement with clinical findings, whereas at in- Linnet K, Olesen OV. Metabolism of clozapine by cDNA-expressed human cytochrome P450enzymes. Drug Metab Dispos 1997; 25: 1379± creasing clozapine concentrations, CYP3A4 takes on a dominat- 1382 ing role [12]. Therefore, the decrease in the plasma concentra- 10 Masubuchi N, Li AP, Okazaki O. An evaluation of cytochrome P450in- tions of clozapine in the presence of omeprazole may be due to duction potential of pantoprazole in primary human hepatocytes. the induction of the cytochrome P450isoenzyme CYP1A2 and/ Chem Biol Interact 1998; 114: 1±13 11 Neuhoff S, Langguth P, Dressler C, Andersson TB, Regardh CG, Spahn- or CYP3A4. Additional effects may arise from omeprazole being Langguth H. Affinities at the verapamil binding site of MDR1-encoded a CYP2C19 substrate and the abundant polymorphism in P-glycoprotein: drugs and analogs, stereoisomers and metabolites. Int CYP2C19, resulting in poor and extensive metabolizers [6]. J Clin Pharmacol Ther 2000; 38: 168±179 12 Poor CYP2C19 metabolizers would be particularily susceptible Olesen OV, Linnet K. Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high to drug interaction resulting from increasing omepraozole con- concentrations. J Clin Pharmacol 2001; 41: 823 ±832 centrations. This may at least partially explain why in case 1 a

Letter ¼ Pharmacopsychiatry 2003; 36: 121±123 13 Robinson M. New generation proton pump inhibitors: overcoming the limitations of early-generation agents. Eur J Gastroenterol Hepatol 2001; 13: 43±47 14 Rost KL, Brösicke H, Brockmöller J. Increase of cytochrome P4501A2 activity by omeprazole: Evidence by the 13C-(N-3-methyl)-caffeine breath test in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1992; 52: 170±180 15 Rost KL, Fuhr U, Thomsen T, Zaigler M, Brockmöller J, Bohnemeier H, Roots I. Omeprazole weakly inhibits CYP1A2 activity in man. Int J Clin Pharmacol Ther 1999; 37: 567±557 16 Stevens I, Glaenz D, Krauss F, Walz G, Gaertner HJ. Bedeutung des the- rapeutischen Drug-Monitoring im Rahmen der Rezidivprophylaxe mit Clozapin. In: Naber D, Müller-Spahn F (eds.). Leponex. Pharmakologie und Klinik eines atypischen Neuroleptikums. Berlin, Heidelberg: Springer, 1999: 79±89 17 Weigmann H, Hiemke C. Determination of clozapine and its major metabolites in human serum using automated solid-phase extraction Letter and subsequent isocratic high-performance liquid chromatography with ultraviolet detection. J Chromatogr 1992; 583: 209 ±216

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Letter¼ Pharmacopsychiatry 2003; 36: 121±123