The Effects Of P-glycoprotein And MDR1 Gene Polymorphisms On The Oral Absorption Of Lansoprazole

Objective:Lansoprazole(Lansoprazole,LPZ) is a proton-pump inhibitor with wide interindividual variation in its pharmacokinetics.Lansoprazole is extensively metabolized by cytochrome P450(CYP2C19).The activity of CYP2C19 depends on the CYP2C19 genptype status.This leads the marked kinetic difference of LPZ.However,the interindividual variation in drug oral absorption can not be explained by the activity of metabolic enzyme.P-glycoprotein(P-gp) is thought to act as an energy dependent 'efflux pump' which expels drug out of cells actively.This mechanism may influence the absorption,distribution and elimination of drugs.It has been well recognized that the significant interindividual variation in the expression and/or function of P-gp,especially in human intestine,which leads to the scattered oral bioavailability of P-gp substrates.In addition,P-gp is coded by MDR1(multi-drug resistant transporter gene).The MDR1 C3435T polymorphism is one of the good markers of the expression and activity of P-gp. Here we try to investigate the inlfuece of P-gp on the absorption of LPZ,maybe as a substrate of P-gp,and the kinetic characteristics of LPZ in subjects who had different genotype status at C3435T position of MDR1,intending to supply the basis information of pharmacokinetics for the dose regimen of LPZ and the indicator of therapeutic efficacy, based on indentification of genotypes.Methods:The intestinal absorption of LPZ in vivo were detected in everted intestine sac absorption model.Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil,cyclosporin A) on in vitro efflux transport of LPZ across the everted small intestine.18 subjects received a single oral dose(30 mg) of LPZ,the pharmacokinetics of LPZ were compared between different genotypes.RRLC-MS/MS methods were established to determine the concemtration of LPZ in intestinal fluid samples and the plasma samples.Genotypes were determined by the PCR-RFLP assay.Statistical comparisons parameters among ABCB1 genotypes were performed by one-way ANOVA.Results:1.Everted intestinal sac absorption studies showed that addition of verapamil(100μg·mL^-1) and cyclopofine A(20μg·mL^-1) in the intestinal perfusate increased the absorption of LPZ to 1.4-fold and 1.8-fold,respectively.These results implicated P-gp is a membrane barrier of LPZ absorption in intestinal route.2.①In present study,the C3435T variation in the MDR1 gene was determined in 18 Chinese subjects.4(22.2%),8(44.4%) and 6(33.3%) subjects had the genotypes of homozygous wild-type 2677GT/3435CC(CC),heterozygous 2677GT/3435CT(CT),and homozygous mutant 2677GT/3435TT(TT),respectively.②The pharmacokinetics parameters including C_max,AUC_0-3h,AUC_0-∞,K_a of LPZ were significantly different within 3 different MDR1 genotypes.For CC,TT and CT groups, C_max of CC group(908.3±130.1 ng.mL^-1) was lower than that of TT(1518.7±324.2 ng·mL^-1) and CT(1645.1±825.7 ng·mL^-1) groups.Aslo,AUC_0-3h was significantly lower in CC group(1384.9±211.2 ng·h/mL) than which was in TT(2722.4±551.9 ng·h/mL) and CT(3159.5±1269.7 ng·h/mL) groups.AUC_0-∞ were 2730.7±503.8 ng·h/mL,4729.1±1384.3 ng·h/mL,7790.5±4283.8 ng·h/mL,respectively,AUC_0-∞ of CC group was the lowest.The ratio of K_a in CC,TT and CT genotypes was 1:2.4:2.8.In the present study,no statistically significant differences in the pharmacokinetic parameters of LPZ were observed between subjects with CT and with TT.Conclusion:MDR1 polymorphisms in exon 26 contributed to LPZ oral absorption.These findings may provide a plausible explanation for interindividual variation in the disposition of LPZ.And compared to subjects with CT or TT genotypes,the absorption of LPZ was lower in subjects with CC genotype.