Anderson Gail D
Health Science Complex H-361A, University of Washington, Seatle, Washington 98195, USA.
Int Rev Neurobiol. 2008;83:1-10. doi: 10.1016/S0074-7742(08)00001-9.
Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions. Is the increased risk due to sex differences in pharmacokinetics, in pharmacodynamics, or did females receive more medications and higher mg/kg doses than males? Recent studies suggest that all of the above may play a role. Generally, males weigh more than females, yet few drugs are dosed based on body weight. Drug concentrations are dependent on the volume of distribution (Vd) and clearance (Cl). Both parameters are dependent on body weight for most drugs independent of sex differences. Females have a higher percent body fat than males which can affect the Vd of certain drugs. Renal clearance of unchanged drug is decreased in females due to a lower glomerular filtration. Sex differences in activity of the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and renal excretion will result in differences in Cl. There is evidence for females having lower activity of CYP1A2, CYP2E1, and UGT; higher activity of CYP3A4, CYP2A6, and CYP2B6; and no differences in CPY2C9 and CYP2D6 activity. Pharmacodynamic changes can affect both the desired therapeutic effect of a drug as well as its adverse effect profile. The most widely reported sex difference is the higher risk in females for drug-induced long QT syndrome, with two-thirds of all cases of drug-induced torsades occurring in females. Females also have a higher incidence of drug-induced liver toxicity, gastrointestinal adverse events due to NSAIDs, and allergic skin rashes. In conclusion, at the minimum, it is important to take into account size and age as well as co-morbidities in determining the appropriate drug regiment for females, as well as males. There are still large gaps in our knowledge of sex differences in clinical pharmacology and significantly more research is needed.
女性已被证明是发生临床相关药物不良反应的一个风险因素。风险增加是由于药代动力学、药效学方面的性别差异，还是女性比男性服用了更多药物且每千克体重剂量更高呢？最近的研究表明上述所有因素可能都起了作用。一般来说，男性体重比女性重，但很少有药物根据体重给药。药物浓度取决于分布容积（Vd）和清除率（Cl）。对于大多数药物而言，这两个参数均取决于体重，与性别差异无关。女性的体脂百分比高于男性，这可能会影响某些药物的Vd。由于肾小球滤过率较低，女性体内原形药物的肾清除率会降低。细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）的酶活性及肾排泄方面的性别差异会导致Cl的差异。有证据表明女性体内CYP1A2、CYP2E1和UGT的活性较低；CYP3A4、CYP2A6和CYP2B6的活性较高；而CPY2C9和CYP2D6的活性没有差异。药效学变化既会影响药物的预期治疗效果，也会影响其不良反应情况。报道最为广泛的性别差异是女性发生药物性长QT综合征的风险更高，所有药物性扭转型室速病例中有三分之二发生在女性身上。女性发生药物性肝毒性、非甾体抗炎药引起的胃肠道不良事件以及过敏性皮疹的发生率也较高。总之，至少在为女性以及男性确定合适的药物治疗方案时，考虑体型、年龄以及合并症很重要。我们在临床药理学性别差异方面的知识仍存在很大差距，需要开展更多的研究。
