中国CYP2C19强代谢者和弱代谢者的兰索拉唑及其代谢产物的药代动力学

Pharmacokinetics of lansoprazole and its metabolites between Chinese CYP2C19 EMs and PMs subjects

目的评价兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜在细胞色素氧化酶CYP2C19强代谢者和弱代谢者中的药代动力学。方法 24例受试者空腹口服兰索拉唑30 mg,用LC-MS/MS法测定14 h内的兰索拉唑及其主要代谢产物的血药浓度,计算药代动力学参数。结果兰索拉唑在强代谢者和弱代谢者中Cmax分别为(901.60±331.70)和(1462.08±390.76)μg.L-1,tmax分别为(1.92±0.63)和(2.50±0.83)h,t1/2分别为(1.21±0.63)和(4.16±1.10)h,AUC0-14分别为(2343.64±1543.05)和(7962.04±2498.39)μg.h.mL-1。5-羟基兰索拉唑在强代谢者和弱代谢者中的Cmax分别为(141.66±59.17)和(40.82±23.01)μg.L-1,tmax分别为(1.83±0.65)和(2.12±0.43)h,t1/2分别为(1.26±0.64)和(3.74±1.74)h,AUC0-14分别为(309.67±113.60)和(158.40±74.60)μg.h.mL-1。兰索拉唑砜在强代谢者和弱代谢者中的Cmax分别为(83.41±60.41)和(287.78±92.77)μg.L-1,tmax分别为(2.15±2.15)和(5.62±2.82)h,t1/2分别为(1.05±0.60)和(12.36±8.49)h,AUC0-14分别为(199.41±288.77)和(2849.17±1095.10)μg.h.mL-1。除兰索拉唑和5-羟基兰索拉唑的tmax外,其余兰索拉唑及其代谢物的药代动力学参数差异有统计学意义(P<0.01)。结论兰索拉唑羟化代谢存在着多态性。CYP2C19弱代谢者的兰索拉唑羟化代谢明显低于CYP2C19强代谢者。

Objective To evaluate the pharmacokinetics of lansoprazole and its two main metabolites in 24 Chinese healthy subjects identified as CYP2C19 EMs or PMs.Methods The plasma concentrations of lansoprazole and its main metabolites were measured by RRLC-MS/MS in 14 h after administration of 30 mg lansoprazole capsule.The pharmacokinetic parameters were calculated by DAS 2.1.1 software.Result The mean Cmax of lansoprazole in CYP2C19 EMs and PMs groups were（901.60±331.70） and（1462.08±390.76）μg·L-1;tmax were（1.92±0.63） and（2.50±0.83）h;t1/2 were（1.21±0.63） and（4.16±1.10）h;AUC were（2343.64±1543.05） and（7962.04±2498.39）μg·h·mL-1,respectively.The differences on the Cmax,t1/2 and AUC of lansoprazole were statistically significant between the EMs and PMs（P0.05）.The mean Cmax of 5-hydroxy lansoprazole in CYP2C19 EMs and PMs groups were（141.66±59.17）and（40.82±23.01） μg·L-1,tmax were（1.83±0.65） and（2.12±0.43） h,t1/2 were（1.26±0.64） and（3.74±1.74） h,AUC were（309.67±113.60） and（158.40±74.60） μg·h·mL-1.The differences on the Cmax,t1/2 and AUC of 5-hydroxy lansoprazole were statistically significant between the Ems and PMs（P0.05）.The mean Cmax of lansoprazole sulphone in CYP2C19 EMs and PMs groups were（83.41±60.41） and（287.78±92.77） μg·L-1,tmax were（2.15±2.15） and（5.62±2.82） h,t1/2 were（1.05±0.60） and（12.36±8.49） h,AUC were（199.41±288.77） and（2849.17±1095.10） μg·h·mL-1.The differences on the Cmax,tmax,t1/2 and AUC of lansoprazole sulphone were statistically significant between the Ems and PMs（P0.05）.Conclusion There is polymorphism in the 5-hydroxylation pathway of lansoprazole which is significantly decreased in CYP2C19 PMs.