title: CYP3A5*3 and MDR1 C3435T are influencing factors of inter-subject variability in rupatadine pharmacokinetics in healthy Chinese volunteers.
abstract: Rupatadine (RUP) is an oral antihistamine and platelet-activating factor antagonist and is shown as the substrate of CYP3A5 and P-gp. The significant interindividual differences of CYP3A5 and P-gp often cause bioavailability differences of some clinical drugs. The present study is aimed to evaluate the effect of genetic polymorphisms of CYP3A5 and MDR1 on RUP pharmacokinetics in healthy male Chinese volunteer subjects. Blood samples were collected from 36 subjects before and after a single, oral RUP 10 mg dose. A PCR-RFLP assay was used to genotype CYP3A5*3 and assess MDR1 C3435T variation. A validated LC-MS/MS method quantified plasma RUP concentration. The relationship between RUP plasma concentration, pharmacokinetic parameters, and polymorphic alleles (CYP3A5 and MDR1) were assessed. Plasma RUP concentrations were lower for CYP3A5*1/*1 carriers than for CYP3A5*3/*3 and CYP3A5*1/*3 carriers. Mean C(max), AUC(0-t) and AUC(0-∞) were significantly lower, and the CLz and Vd were significantly higher in the CYP3A5 wild-type group, than in the CYP3A5 mutated group. MDR1 CT and MDR1 TT carriers had lower plasma RUP concentrations than MDR1 CC carriers. The mean C(max), AUC(0-t), AUC(0-∞) and T max were significantly lower in the TT group than in the CC and CT groups. The mean CLz was higher in the TT group than in the CC and CT groups, but not significantly. These results suggest that CYP3A5 and MDR1 may play a key role in the variability of RUP metabolism and transport, respectively. CYP3A5 and MDR1 polymorphisms may be the main explanation for the differences observed in RUP pharmacokinetics, and therefore may provide a rationale for safe and effective clinical use of RUP. Our research lays down a solid theory foundation to guide the safe and effective clinical use of RUP and a route to achieve individualized therapy.
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China. xiongyuqing2009@hotmail.com.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.|The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Yang
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Xia
authors.affiliation: The School Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Huang
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Clinical Pharmacology Institute, Nanchang University, Bayi Road 461#, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D014838:Volunteers
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C103639:rupatadine; D003533:Cyproheptadine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A5; MDR1; Pharmacokinetics; Polymorphisms; Rupatadine