美多心安在中国健康人群的代谢研究

STUDY ON METOPROLOL METABOLISM IN A CHINESE POPULATION OF HEALTHY VOLUNTEERS

本研究通过应用HPLC定量分析健康志愿者口服单剂100mg 美多心安酒石酸盐后0—8h尿中美多心安(M)、α-羟基美多心安(HM)和美多心安酸(MA),测定美多心安α-羟化和氧位去烃基化一氧化代谢能力、肾脏排泄美多心安的能力。在100位健康志愿者,美多心安α-羟化的代谢比值(MR,0—8h尿中M/HM)的对数值呈现双态性分布,分界点(antimode)为1.09。98位快代谢者(EMs)M/HM介于0.34—12.28(中位数1.94),2位慢代谢者(PMs)M/HM分别高达306.0和640.3。氧位去烃基化—氧化的代谢比值(M/MA)介于0.050—0.715(中位数0.198),2位PMs的M/MA分别为0.406和0.575,M/MA 的对数值虽属单态性分布,但是在M/HM和M/MA两种代谢比值之间具有非常显著的相关性(r_s=0.95,p<0.001)。在EMs(PMs)0—8h尿中美多心安、HM、MA回收率分别为7.4±4.1(10.2±1.4)%、3.8±1.8(0.03±0.02)%和35.9±11.0(21.1±2.2)%。结果表明,美多心安α-羟化代谢PMs在中国人群的频发率约为2%,与近年来报道异喹胍4-羟化PMs在中国人群的频发率(1—1.4%)相似,但明显低于Mc-Gourty等所报道白种人群的8.4%;在PMs氧位去烃基化—氧化代谢也较慢;上述两种代谢的频数分布曲线右移,可能主要与中国人群肾脏排泄原形美多心安的能力较强有关。

The capacity for metoprolol α-hydroxylation, O-dealkylation oxidation and renal excretion was determined by HPLC measuring concentrations of metoprolol(M), α-hydroxymetoprolol (HM) and metoprolol acid(MA)in 0-8h urine after an ora1 Single dose of 100mg metoprolol tartrate.In100 healthy volunteers, for α-hydroxylation of metoprolol the distribution of the log M/HM 8 h urinary ratio was bimodal and 2 poor metabolisers(PMs) were identified (antimode 1 .09). The median M/HM ratio was 1 .94(range 0. 34-12.28) in 98 extensive metabolisers (EMs) ; the M/HM valueswere 306. 0 and 640. 3 in 2 PMs respectively. For O-dealkylation-oxidation ofmetoprolol the distribution of the log M/MA 8h urinary ratio was unimodal(the median M/MA ratio was 0. 198 (range 0.050-0. 715) ), however, therewas a significant high correlation between the M/HM and M/MA ratios (r_s=0.95, p<0.001), and the values for the M/MA ratio in PMs (being 0.406and 0.575 respectively) were at the upper end of the range. The results suggest: (1 )e incidence of PMs of metoprolol α-hydroxylation in Chinese population is about 2%, which is similar to those(1-1 .4%)of debrisoquine 4-hydroxylation in Chinese populations reported recently,but much lower than the 8.4% in Caucacian population reported by McGourty; (2)the O-dealkylation-oxidation of metoprolol is poorer in PMs than in EMs, (3) compared with those in Caucacian, the frequency distribution curves of metoprolol α-hydroxylation and 0-dealkylation-oxidation shifts to right,the main reason is probably related to a higher capacity for the kidney to excrete unchanged metoprolol in Chinese.