ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients.

AIMS ABCB1 is a transmembrane transporter that is expressed in excretory organs (kidneys and liver), in intestine mucosa and on the blood-brain barrier. Because of the particular distribution of the protein, the activity of ABCB1 may significantly affect drug pharmacokinetics during absorption and distribution. Of note, several SNPs of ABCB1 are known and many of them affect transporter activity and/or expression. In this view, changes in the pharmacokinetics of drugs that are ABCB1 substrates could be clinically relevant and the evaluation of ABCB1 SNPs should deserve particular attention. Therefore, the aim of the present study was to investigate the possible association between ABCB1 polymorphisms and clozapine plasma levels in psychotic patients. MATERIALS & METHODS c.1236C>T (exon 12), c.2677G>T (exon 21) and c.3435C>T (exon 26) SNPs of ABCB1 were evaluated by PCR techniques, while plasma levels of clozapine and norclozapine were measured by HPLC in 40 men (aged, 47.6 +/- 16.6 years, median: 42 years) and 20 women (aged 40.7 +/- 11.4 years, median: 38 years) 1 month after the start of clozapine administration. RESULTS A total of three SNPs were in Hardy-Weinberg equilibrium, with a calculated frequency of the wild-type alleles of 0.54, 0.55 and 0.45 for SNPs on exons 12, 21 and 26, respectively. Patients with c.3435CC or c.2677GG genotypes had significantly lower dose-normalized clozapine levels than those who were heterozygous or TT carriers. More interestingly, c.3435CC patients (15 subjects) needed significantly higher daily doses of clozapine (246 +/- 142 mg/day) compared with the remaining 24 CT and 21 TT patients (140 +/- 90 mg/day) in order to achieve the same clinical benefit. CONCLUSION c.3435CC patients require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients, and ABCB1 genotyping should be considered as a novel strategy that should improve drug use.

[1]  V. Haufroid,et al.  1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation , 2007, Pharmacogenetics and genomics.

[2]  S. Duan,et al.  Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. , 2006, Pharmacogenomics.

[3]  W. M. Smit,et al.  Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel , 2006, Clinical Cancer Research.

[4]  W. Koch,et al.  CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing , 2006, The Pharmacogenomics Journal.

[5]  M. Fromm,et al.  The role of the transporter P-glycoprotein for disposition and effects of centrally acting drugs and for the pathogenesis of CNS diseases , 2006, European Archives of Psychiatry and Clinical Neuroscience.

[6]  G. Burckart,et al.  Pharmacogenetics in Transplant Patients: Can it Predict Pharmacokinetics and Pharmacodynamics? , 2006, Therapeutic drug monitoring.

[7]  Ellen B. Wolpert,et al.  Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells , 2005, Neuropharmacology.

[8]  S. Cole,et al.  Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. , 2005, Toxicology and applied pharmacology.

[9]  J. van der Weide,et al.  The cytochrome P450 CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic patients , 2005, Annals of clinical biochemistry.

[10]  M. Stephens,et al.  Accounting for Decay of Linkage Disequilibrium in Haplotype Inference and Missing-data Imputation , 2022 .

[11]  Laurent Excoffier,et al.  Arlequin (version 3.0): An integrated software package for population genetics data analysis , 2005, Evolutionary bioinformatics online.

[12]  Xi Chen,et al.  THE IMPACT OF P-GLYCOPROTEIN ON THE DISPOSITION OF DRUGS TARGETED FOR INDICATIONS OF THE CENTRAL NERVOUS SYSTEM: EVALUATION USING THE MDR1A/1B KNOCKOUT MOUSE MODEL , 2005, Drug Metabolism and Disposition.

[13]  Christoph Hiemke,et al.  Identification of P‐glycoprotein substrates and inhibitors among psychoactive compounds — implications for pharmacokinetics of selected substrates , 2004, The Journal of pharmacy and pharmacology.

[14]  D. Goldstein,et al.  Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene. , 2004, Genome research.

[15]  G. Simpson,et al.  Plasma clozapine concentration coefficients of variation in a long-term study , 2004, Schizophrenia Research.

[16]  Matthias J. Müller,et al.  Therapeutic Monitoring of New Antipsychotic Drugs , 2004, Therapeutic drug monitoring.

[17]  Amin Rostami-Hodjegan,et al.  Influence of Dose, Cigarette Smoking, Age, Sex, and Metabolic Activity on Plasma Clozapine Concentrations: A Predictive Model and Nomograms to Aid Clozapine Dose Adjustment and to Assess Compliance in Individual Patients , 2004, Journal of clinical psychopharmacology.

[18]  F. Itoh,et al.  Detection of the four sequence variations of MDR1 gene using TaqMan MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects. , 2003, Clinical biochemistry.

[19]  Yuichi Sugiyama,et al.  Impact of Drug Transporter Studies on Drug Discovery and Development , 2003, Pharmacological Reviews.

[20]  D. Castle,et al.  Serum Clozapine Levels: A Review of Their Clinical Utility , 2003, Journal of psychopharmacology.

[21]  M. Bottai,et al.  Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study. , 2003, The Journal of clinical psychiatry.

[22]  D. Goldstein,et al.  Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. , 2003, The New England journal of medicine.

[23]  M. Fromm.  The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. , 2002, Advanced drug delivery reviews.

[24]  J. Volavka,et al.  Optimal Dosing of Atypical Antipsychotics in Adults: A Review of the Current Evidence , 2002, Harvard review of psychiatry.

[25]  J. Markowitz,et al.  In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. , 2002, Life sciences.

[26]  P. Jolliet,et al.  Evidence from a population pharmacokinetics analysis for a major effect of CYP1A2 activity on inter- and intraindividual variations of clozapine clearance , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[27]  C. Martini,et al.  Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients Influence of patient-related variables , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[28]  M. Fromm,et al.  The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. , 2001, Pharmacogenetics.

[29]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[30]  H. McLeod,et al.  MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. , 2001, Pharmacogenetics.

[31]  C. Meisel,et al.  Frequency of single nucleotide polymorphisms in the P‐glycoprotein drug transporter MDR1 gene in white subjects , 2001, Clinical pharmacology and therapeutics.

[32]  A Rzhetsky,et al.  The human ATP-binding cassette (ABC) transporter superfamily. , 2001, Journal of lipid research.

[33]  G. Cassano,et al.  Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study. , 2000, The Journal of clinical psychiatry.

[34]  D. Collier,et al.  Pharmacogenetic prediction of clozapine response , 2000, The Lancet.

[35]  U. Brinkmann,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. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  F. Bressolle,et al.  Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia. , 1998, Journal of clinical psychopharmacology.

[37]  Stephan Arndt,et al.  Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram , 1998, Biological Psychiatry.

[38]  A. Schinkel,et al.  P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. , 1996, The Journal of clinical investigation.

[39]  G Honigfeld,et al.  Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. , 1988, Archives of general psychiatry.

[40]  E. Spina,et al.  Metabolic drug interactions with newer antipsychotics: a comparative review. , 2007, Basic & clinical pharmacology & toxicology.

[41]  C. Advokat.  Differential effects of clozapine versus other antipsychotics on clinical outcome and dopamine release in the brain. , 2005, Essential psychopharmacology.

[42]  G. Remington,et al.  Augmentation Strategies in Clozapine-Resistant Schizophrenia , 2005, CNS drugs.

[43]  W. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.

[44]  I. Pastan,et al.  Expression of a multidrug-resistance gene in human tumors and tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.