The Influence of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Silodosin in Healthy Chinese Volunteers

Abstract

Silodosin (KMD-3213), a highly selective α1a-adrenergic receptor antagonist, was approved in Japan (2006), the United States of America (2008), and China (2011) for benign prostatic hyperplasia. Silodosin was a dual substrate for CYP3A and P-glycoprotein, and two main metabolites were generated in plasma by UDP-glucuronosyltransferase (UGT) and alcohol/aldehyde dehydrogenase. To examine the effect of genetic polymorphisms on silodosin pharmacokinetics in healthy male Chinese subjects after a single oral dose. Blood samples were collected from subjects (n = 31) at scheduled time intervals before and after an oral administration of 4 mg silodosin. A validated LC/MS/MS method was used to quantify the plasma silodosin concentration. The relationship between plasma silodosin concentration, its pharmacokinetic parameters, polymorphic alleles (UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4, and CYP3A5), and other enzymes related to silodosin metabolism were assessed for each subject. Subjects with UGT2B7*1/*2 and *2/*2 had a 27.1% and 22.7% longer terminal t(1/2) (respectively), 37.9% and 25.2% larger AUC(0-∞) (respectively), slower silodosin metabolism, and increased silodosin exposure, when compared to the subjects with UGT2B7*1/*1. The silodosin T(max) was affected by CYP3A5 (p < 0.05) with a slower time to reach C(max) for subjects with the CYP3A5*1/*1 polymorphism when compared to those with the *1/*3 or *3/*3 polymorphisms. The C(max) was affected by CYP3A4 (p < 0.05) with a lower C(max) for subject with the CYP3A4*18B/*18B compared to those with the *1/*1 and *1/*18B. UGT2B7 may play a key role in the variability observed in silodosin metabolism.