Polymorphisms in CYP1A1 and CYP3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting.
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 CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism.



This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women.



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.



Of 16 patients, 25% were homozygous for the allele variant CYP3A5*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 CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes.



Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women.
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
Martha L
ML
Bustos
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
Yang
Y
Zhao
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
Huijun
H
Chen
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Steve N
SN
Caritis
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Raman
R
Venkataramanan
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D002853:Chromatography, Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D017829:Granisetron / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D048968:Morning Sickness / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D000932:Antiemetics; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D017829:Granisetron; C513055:ABCB1 protein, human; C569463:CYP1A1 protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human
cytochrome *P450 enzymes; granisetron; nausea and vomiting; polymorphism; pregnancy