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Effect of ABCB1 C3435T polymorphism on pharmacokinetics of antipsychotics and antidepressants

AuthorsSaiz-Rodríguez, Miriam; Belmonte, Carmen; Román, Manuel; Ochoa, Dolores; Jiang-Zheng, Carolina; Koller, Dora; Mejía, Gina; Zubiaur, Pablo; Wojnicz, Aneta; Abad-Santos, Francisco
Issue Date2018
PublisherJohn Wiley & Sons
CitationBasic and Clinical Pharmacology and Toxicology 123(4): 474-485 (2018)
AbstractP‐glycoprotein, encoded by ABCB1, is an ATP‐dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P‐glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real‐time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9‐OH‐risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro‐aripiprazole and trazodone area under the concentration‐time curve, along with lower half‐life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro‐aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P‐glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.
Publisher version (URL)https://doi.org/10.1111/bcpt.13031
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