Abstract：
AIMS:Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N-oxide (CLZ-NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites. METHODS:Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used. RESULTS:Km and Vmax values determined in human liver microsomes were lower for the demethylation (61 +/- 21 microM, 159 +/- 42 pmol min(-1) mg protein(-1) mean +/- s.d.; n = 4), than for the N-oxidation of CLZ (308 +/- 1.5 microM, 456 +/- 167 pmol min(-1) mg protein(-1); n = 3). Formation of DCLZ was inhibited by fluvoxamine (53 +/- 28% at 10 microM), triacetyloleandomycin (33 +/- 15% at 10 microM), and ketoconazole (51 +/- 28% at 2 microM) and by antibodies against CYP1A2 and CYP3A4. CLZ-NO formation was inhibited by triacetyloleandomycin (34 +/- 16% at 10 microM) and ketoconazole (51 +/- 13% at 2 microM), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ-NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ-NO. Km and Vmax values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions. CONCLUSIONS:It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N-oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Eiermann B,Engel G,Johansson I,Zanger UM,Bertilsson Ldoi
10.1046/j.1365-2125.1997.t01-1-00605.xsubject
Has Abstractpub_date
1997-11-01 00:00:00pages
439-46issue
5eissn
0306-5251issn
1365-2125journal_volume
44pub_type
杂志文章abstract：:Eight psoriatic patients were treated with etretinate (50 mg daily) for 6 weeks. Skin chamber exudates from involved and uninvolved skin were assayed for arachidonic acid, 12-HETE, PGE2 and for neutrophil chemokinetic activity co-chromatographing with leukotriene B4, before and at weekly intervals during therapy. Pre-...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02499.x
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abstract：:Simultaneous cerebrospinal fluid (CSF), total and free plasma valproic acid (VPA) concentrations were measured in 17 patients receiving two weight-adjusted VPA doses as seizure prophylaxis prior to diagnostic myelography or cisternography. Free drug concentrations were similar when measured by equilibrium dialysis (ED...
journal_title：British journal of clinical pharmacology
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doi：10.1111/j.1365-2125.1983.tb02179.x
更新日期：1983-10-01 00:00:00
abstract：AIMS:6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharma...
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abstract：:The acute peripheral vascular and diuretic effects of intravenous frusemide 10 mg and 20 mg were compared with those of bumetanide 250 micrograms and 500 micrograms in a group of 10 salt depleted volunteers. Significant reductions in forearm blood flow (FBF) were observed after frusemide 10 mg (-0.77 ml 100 ml-1 min-1...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1986.tb05207.x
更新日期：1986-04-01 00:00:00
abstract：:1. Alfuzosin is a post-synaptic alpha-adrenoceptor antagonist with antihypertensive and peripheral vasodilator properties. 2. We measured the effect of alfuzosin, 5 mg, on sympathetically-mediated venoconstriction by changes in the venous reflex response (VRR) in a randomised, double-blind, placebo-controlled, crossov...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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abstract：AIMS:The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,多中心研究,随机对照试验
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pub_type： 杂志文章
doi：10.1111/j.1365-2125.2011.04010.x
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journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1995.tb04429.x
更新日期：1995-02-01 00:00:00
abstract：AIM:We compared the pharmacokinetic (PK) profiles of co-crystal of tramadol-celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. METHODS:Healthy adults aged 18-50 years received, under fasted conditions, 15 twice-daily doses of the following treatmen...
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pub_type： 杂志文章,随机对照试验
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abstract：INTRODUCTION:Irrational medicine use is a global crisis, but incidences are proportionately higher in low and middle-income countries like Sierra Leone. This study explores the structure, functions, and challenges of Drug and Therapeutics Committees (DTC) an intervention towards irrational medicines use recently pilote...
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pub_type： 杂志文章,评审
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abstract：:1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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更新日期：1996-10-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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更新日期：2005-02-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1988.tb05283.x
更新日期：1988-09-01 00:00:00
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journal_title：British journal of clinical pharmacology
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doi：10.1111/j.1365-2125.1989.tb05438.x
更新日期：1989-09-01 00:00:00
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pub_type： 临床试验,杂志文章,多中心研究
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journal_title：British journal of clinical pharmacology
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journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
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更新日期：1988-05-01 00:00:00
abstract：AIMS:5-HT1B-receptor mediated vasoconstriction of cranial arteries is a potential mechanism by which 5-HT1B/1D-receptor agonists such as sumatriptan produce their antimigraine effects. 5-HT1B-receptors exist in other blood vessels which may give rise to unwanted vascular effects. Therefore we examined the distribution ...
journal_title：British journal of clinical pharmacology
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doi：10.1046/j.0306-5251.2001.01536.x
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journal_title：British journal of clinical pharmacology
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doi：10.1111/j.1365-2125.1985.tb05042.x
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更新日期：2020-08-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/j.1365-2125.1989.tb03449.x
更新日期：1989-06-01 00:00:00
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journal_title：British journal of clinical pharmacology
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doi：
更新日期：1993-02-01 00:00:00
