Czerniak R
Metabolism and Pharmacokinetics, Primedica Inc., Worcester, Massachusetts 01608, USA.
Int J Toxicol. 2001 May-Jun;20(3):161-3. doi: 10.1080/109158101317097746.
The study of gender-based differences in the pharmacokinetics (PK) of compounds tested in animal models has received greater attention in recent years. As early as 1932, the pharmacological action of barbiturates was recognized as gender dependent-female rats required half the dose needed by male rats to induce sleep. Later, it was shown that gender differences in hepatic metabolism were responsible for this gender-related pharmacodynamic response. Today, it is well known that gender-dependent metabolism in rats often results from differences in expression of hepatic enzymes. The sex-specific cyctochrome P450s CYP2C11, CYP2C13, and CYP3A2 are expressed in males whereas CYP2C12 is expressed in females. Most of the known gender-related differences in toxicity of compounds in rats are due to gender-related hepatic metabolism differences. It is clear that compounds may undergo gender-dependent metabolism; it is also true that the fundamental PK parameters of clearance (CL) and volume (V) can demonstrate a gender dependence in a wide variety of animal species: rats, mice, rabbits, hamsters, dwarf goats, cattle, and rainbow trout. To appreciate how gender-related differences affect PK parameters, it is necessary to have a basic understanding of the factors that control the PK of compounds. Changes in these factors will be related to the primary PK parameters of CL and V. A review of the literature provides examples of gender-based differences in these factors and examples of the observed differences in the PK profile of the administered compound. Examples of gender-based differences in the PK of compounds leading to gender differences in the toxicity in nonclinical test species are also discussed.
近年来，在动物模型中测试的化合物的药代动力学（PK）方面基于性别的差异研究受到了更多关注。早在1932年，巴比妥类药物的药理作用就被认为具有性别依赖性——雌性大鼠诱导睡眠所需的剂量是雄性大鼠的一半。后来发现，肝脏代谢中的性别差异是这种与性别相关的药效学反应的原因。如今，众所周知，大鼠中性别依赖性代谢通常源于肝酶表达的差异。性别特异性细胞色素P450s CYP2C11、CYP2C13和CYP3A2在雄性中表达，而CYP2C12在雌性中表达。大鼠中已知的大多数与性别相关的化合物毒性差异是由于与性别相关的肝脏代谢差异。显然，化合物可能会经历性别依赖性代谢；同样，清除率（CL）和体积（V）等基本药代动力学参数在多种动物物种（大鼠、小鼠、兔子、仓鼠、矮山羊、牛和虹鳟鱼）中也可表现出性别依赖性。为了理解与性别相关的差异如何影响药代动力学参数，有必要对控制化合物药代动力学的因素有基本的了解。这些因素的变化将与CL和V的主要药代动力学参数相关。文献综述提供了这些因素中基于性别的差异的例子，以及所给药化合物药代动力学特征中观察到的差异的例子。还讨论了化合物药代动力学中基于性别的差异导致非临床测试物种毒性出现性别差异的例子。
