ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients. (August 2009)

• Record Type: Journal Article
• Authors: Consoli, Giorgio; Lastella, Marianna; Ciapparelli, Antonio; Dell''Osso, Mario Catena; Ciofi, Laura; Guidotti, Emanuele; Danesi, Romano; Dell''Osso, Liliana; Del Tacca, Mario; Di Paolo, Antonello
• Is Part Of: Pharmacogenomics. Volume 10:Number 8(2009)
• Page Start: 1267
• Page End: 1276
• Publication Date: 2009-08
• Subjects: ABCB1 -- polymorphisms -- clozapine -- plasma levels; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.09.51
• Languages: English
• ISSNs: 1462-2416

Abstract

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.