Gender differences in metabolism

It should always be kept in mind, particularly in humans that there can be significant gender based differences in metabolism (Mugfor and Kidderis, 1998). Particularly for drugs where there is a significant potential for disproportionate use by women, FDA expects early evaluation of this aspect. 

A brief review of pharmacokinetic principles will place the available data on gender differences in context. Bioavailability, which refers to the amount of drug eventually reaching the systemic circulation, is influenced by absorption, metabolism in the gastrointestinal tract, and the hepatic first-pass effect. The impact of the first-pass effect is greater for drugs that have high hepatic... 

After the drug is absorbed, it may be taken up by hepatocytes and metabolized, a process that is referred to as the hepatic first-pass effect. If the compound is highly extractable, then the amount of drug removed is high and the degree of available drug is lowered. It is not known whether there are gender differences in hepatic blood flow that can influence the extraction rate of some medications. 

Schmidt. M.E., Matochik, J.A., Goldstein, D.S., et al. Gender differences in brain metabolic and plasma catecholamine responses to alpha2-adrenoceptor blockade. 

Hayes FJ, Fiad TM, McKenna TJ. Gender difference in the response of growth hormone (GH)-deficient adults to GH therapy. Metabolism 1999 48(3) 308-13. 

Many differences in overall toxicity between males and females of various species are known (Table 9.1). Although it is not always known whether metabolism is the only or even the most important factor, such differences may be due to gender-related differences in metabolism. Hexobarbital is metabolized faster by male rats thus female rats have longer sleeping times. Parathion is activated to the cholinesterase inhibitor paraoxon more rapidly in female than in male rats, and thus is more toxic to females. Presumably many of the gender-related differences, as with the developmental differences, are related to quantitative or qualitative differences in the isozymes of the xenobiotic-metabolizing enzymes that exist in multiple forms, but this aspect has not been investigated extensively. 

Drug Discovery Today 7 25-27 Li AP (2004) In vitro approaches to evaluate ADMET drug properties. Curr Top Med Chem 4 701-706 Li W, Escarpe PA, Eisenberg EJ et al. (1998) Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrobial Agents and Chemotherapy 42 647-653 Los LE, Welsh DA, Herold EG et al. (1996) Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity observations from a chronic (27-week) toxicity study of enalapril/diltiazem combinations in rats. Drug Metab Dispos 24 28-33... 

Los LE, Welsh DA, Herold EG et al. (1996) Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity observations from a chronic (27-week) toxicity study of enalapril/ditiazem combinations in rats. Drug... 

Rane A (1999) Phenotyping of drug metabolism in infants and children Potentials and problems. Pediatrics 104 640-643 Relling MV, Lin JS, Ayers GD, Evans EE (1992) Racial and gender differences in N-acetyltransferase, xanthine oxidase and CYP1A2 activities. Clin Pharmacol Ther 52 643-658... 

The route of administration of the test compound should ensure a relevant target exposure and in the case of pharmaceuticals it should consider the application route in humans. Each treated and control group must include at least 5 animals that can be analyzed per sex. It is possible to use only one gender if it can be demonstrated that no substantial differences in metabolism,... 

The gender difference in pellagra (Section 8.5) suggests that endogenous estrogens may have an effect on tryptophan metabolism similar to tbat of exogenous estrogens used as contraceptives. It implies that not only is the... 

Species/gender differences in tumor incidence, toxicokinetics (AUC), protein binding, and metabolism... 

Although these sex-related differences in metabolism have been known for a long time, there is very little data available concerning the role of gender in the metabolism and pharmacokinetics of drugs of abuse. For some drugs of abuse, sexual dimorphism could have important implications and adverse consequences. For PCP, a subject of this discussion, metabolism is the major mechanism for inactivation of pharmacological effects (Mayersohn 1985). In... 

Other covariates that have been identified as important in pediatric PM studies include the level of metabolism in the gastrointestinal tract, ECMO that may be a marker of hypoperfusion, nutrition, and genetics-genomics. Ethnic differences may also exist in pediatric populations while known gender differences in adults are likely absent or greatly reduced. 

Several reports have described gender differences in the toxicokinetics and the toxicodynamics of MeHg. Evidence of gender-dependent MeHg metabolism has been reported in humans (Miettinen 1973) and... 

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