Gender-Based Differences in Pharmacokinetics in Laboratory Animal Models

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.