Gender-related differences in pharmacokinetics and their clinical significance

Abstract

SUMMARYmay involve differences in physical constitution (body water space, muscle mass, organ blood flow and organ In this review I have attempted to summarize gender function) and physiology (menopause, pregnancy and differences in pharmacokinetics involving the cytomenstruation) between women and men. In addition, chrome P450 (CYP) isozymes of young and mature as hormonal steroid contraceptives are used by some adults, excluding the effects of the menstrual cycle, women, therapeutic drugs for use by pregnant women, use of oral contraceptives and pregnancy. Sex difin particular, should be restricted because of obvious ferences in drug metabolism and elimination are ethical considerations other than age. Thus, the pharmainly related to steroid hormone levels. CYP3A4, macokinetics and pharmacodynamics of many drugs responsible for the metabolism of over 50% of theramay well be different due to a variety of causal factors peutic drugs, exhibits higher activity in women than (Fig. 1). in men. Nonetheless, the absence of a sex difference Cytochrome P450 (P450 or CYP) is involved in drug has been reported by some workers. The activity metabolism, but can be divided into many subfamilies, of several other CYP (CYP2C19, CYP2D6, CYP2E1) e.g. CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4, each of which isozymes and the conjugation (glucuronidation) is linked to a different set of drugs, and numerous activity involved in drug metabolism may be higher reviews have been published on this topic (8-26). Some in men than in women. Drug metabolism in women drugs, such as S-mephenytoin, catalysed by CYP2C19 is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

“…Sex‐related pharmacokinetic disparities have been reported for other drugs. There are many potential reasons for sex differences in CC‐292 pharmacokinetics, such as differences in gastric pH, which is higher in females, lower hepatic blood flow and consequently lower hepatic metabolic capacity,22, 23 which could partly explain the findings. However, the resulting differences in drug exposures between female and male subjects were small (below 26%) relative to the observed overall variability in the pharmacokinetics of CC‐292.…”

Effect of breed and gender on bovine liver cytochrome P450 3A (CYP3A) expression and inter-species comparison with other domestic ruminants

“…Many studies have mapped out the molecular biology of this superfamily and nowadays it can be divided into many subfamilies, each of which (particularly those belonging to numbers 1 to 4) is linked to a different set of drugs [33,56]; moreover, numerous investigators have identified the substrate specificities of each single isoform [33]. Recently, some studies which report the metabolism of substrates as models for specific enzymatic pathways in liver preparations of farm animals have been published too [29,37,49,55].…”

“…liver, intestine), wide substrate spectrum, susceptibility to drug interactions as well as interindividual variable expression levels [3,12,31,56].…”

Characterization of the Tissue Distribution of the MouseCyp2cSubfamily by Quantitative PCR Analysis

“…Identifying these sexually dimorphic mouse Cyp2c enzymes in liver may aid in understanding differences in drug potency observed in male versus female mice. However, sexual dimorphism is much less pronounced in human models in comparison with rodent models (Lofgren et al, 2008;Tanaka, 1999), which must be taken into account when using the mouse as a model for human disease and drug metabolism.…”