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Polymorphisms in CYP 1A1 and CYP 3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting
Author(s) -
Bustos Martha L.,
Zhao Yang,
Chen Huijun,
Caritis Steve N.,
Venkataramanan Raman
Publication year - 2016
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1860
Subject(s) - granisetron , nausea , single nucleotide polymorphism , antiemetic , pharmacology , pharmacokinetics , pharmacogenetics , cyp3a5 , medicine , genotype , vomiting , cyp2c9 , cyp2d6 , endocrinology , anesthesia , gastroenterology , biology , cytochrome p450 , metabolism , genetics , gene
Background Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 ( CYP ) enzymes CYP 1A1 and CYP 3A and is likely a substrate of the ABCB 1 transporter. Single‐nucleotide polymorphisms ( SNP s) in CYP 3A, CYP 1A1 , and ABCB 1 can alter drug metabolism. Objective This study evaluated the influence of polymorphisms in CYP 3A4 , CYP 3A5 , CYP 1A1, and ABCB 1 on the pharmacokinetic properties of granisetron in pregnant women. Methods The study enrolled 16 pregnant women (gestational age of 12–19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem–mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy–Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Results Of 16 patients, 25% were homozygous for the allele variant CYP 3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration–versus–time curve ( AUC ) compared with nonhomozygous patients. Approximately one‐third of patients (n=5) were carriers for the allele variant CYP 1A1*2A and had a significantly higher granisetron clearance and decreased AUC . We did not find significant differences in the AUC or clearance for any SNP s in CYP 3A4 and ABCB 1 genes. Conclusions Polymorphisms in CYP 3A5 and CYP 1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women.