Pharmacogenetics of Drugs Withdrawn From the Market

Wei Zhang; Mary W Roederer; Wang-Qing Chen; Lan Fan; Hong-Hao Zhou


Pharmacogenomics. 2012;13(2):223-231. 

In This Article


Sibutramine is an appetite suppressant, blocking the uptake of norepinephrine, serotonin and dopamine. In November of 1997, sibutramine was approved by the FDA for long-term weight loss and soon became available in more than 20 markets in the world. In October 2010, following a benefit–risk assessment of sibutramine, which showed that sibutramine can increase cardiovascular risks, which outweigh the benefit of weight loss in patients, Abbott agreed to recall sibutramine in the USA.[4] It was reported that sibutramine was metabolized by CYP2B6, CYP3A4 and CYP2C19 to the active metabolites M1 or M2.[5] CYP2B6 and CYP3A4 have a high degree of genetic polymorphisms. The studies showed, compared with CYP2B6 wild-type, the average blood concentration of sibutramine increased 252%, and the metabolites increased 148% in variants.[5] Research also indicated that CYP2B6*6 (rs3745274 and rs2279343) can significantly increase the elimination time of the active metabolite M1 (M1t1/2 33.3 ± 10.5 h vs 21.0 ± 7.4 h; *1/*6 vs *1/*1; p = 0.0001).[6] Studies performed in Asian populations showed that the CYP2C19 genotype substantially affects the pharmacokinetics of sibutramine (poor metabolizers [PMs] had plasma sibutramine levels almost 2.5-times higher than extensive metabolizers [EMs]).[7]In vitro studies demonstrated that sibutramine preferentially inhibits the hERG potassium channel in a concentration-dependent manner, an effect that may contribute to prolonging the cardiac action potential duration associated with LQTS.[8] So, the significant increase in drug concentration may influence the occurrence of LQTS. Otherwise, the mutations of KCNQ1 C793T, which were likely to prolong cardiac membrane depolarization and increase susceptibility to LQTS.[9] Besides, Hsiao et al. approved that compared with the placebo group, patients carrying the GNβ3 825C>T (rs5443) TT/TC genotype who had taken sibutramine lost weight markedly (7.4 ± 1.4 kg vs 3.4 ± 1.2 kg; p < 0.001), while carriers of the CC genotype did not have significant weight loss (p = 0.078).[10]


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