Sex, differences in drug metabolism

Sizer AR, Long SK, Roberts MHT A modulatory function of 5-hydroxytryptamine in the central nervous system, in Serotonin, CNS Receptors and Brain Function (Advances in the Biosciences, Vol 85). Edited by Bradley PB, Handley SL, Cooper SJ, et al. Oxford, England, Pergamon, 1992, pp 135-146 Skett P Biochemical basis of sex differences in drug metabolism. Pharmacol TTier 38 269-304, 1988... 

The effects of sex on drug disposition and pharmacokinetics have been incompletely evaluated but may be significant. In addition/ the contribution of sex differences is sometimes difficult to separate from the major complicating effects of dietary and environmental inducers and inhibitors on drug-metabolizing enzymes. Sex differences in drug metabolism are considered in detail in Chapter 21. 

Drug metabolism is a primary mechanism for removal of drugs from the body. Drug metabolism may be affected by age, disease state, polymorphism, and inhibition or induction of drug-metabolizing enzymes. Sex differences in drug metabolism are minor in humans and usually are not clinically important. 

Adrenalectomy in male rats impairs the metabolism of hexobarbital and other foreign compounds by enzymes in hepatic microsomes this effect can be reversed by injections of cortisone, cortisol, or prednisolone. There is a marked sex difference in rats in the effect of adrenalectomy on the metabolism of drugs by microsomal enzymes. In male rats, adrenalectomy impairs the metabolism of hexobarbital and aminopyrine but has no effect on the metabolism of aniline or zoxazolamine. On the other hand, adrenalectomy in female rats has little influence on the metabolism of these substrates. It should be recalled that hexobarbital and aminopyrine display a pronounced (2- to 3-fold) sex difference in their metabolism in rats whereas aniline and zoxazolamine have little or no sex difference. Therefore, a prominent effect of adrenalectomy is reduction in the magnitude of the sex difference in drug metabolism. 

The sex difference in the metabolism of drugs has not been observed in human beings. However, in rats, the pharmacological activity of a drug is more prolonged and the toxicity more marked in females than males, a difference which has been attributed to the more rapid metabolism of the drugs by the hepatic microsomal enzymes of the male rat. 

R. Kato, Sex related differences in drug metabolism. Drug Metab. Rev. 3 1, 1974. 

In adult rats, the magnitude of the sex difference in microsomal drug metabolism is dependent upon the drug substrate examined. Microsomes from male rats are 3 to 4 times as active as those from females in the metabolism of ethyl-morphine, hexobarbital, and aminopyrine, but only about twice as active in the metabolism of cocaine or p-nitroanisole. There is no appreciable sex difference in the metabolism of zoxazolamine or aniline by rat-liver microsomes nor in the duration of zoxazolamine paralysis in vivo. Similarly, there is very little sex difference in the cytochrome P-4S0 content or in NADPH cytochrome c reductase activity. 

Pohl LR, George JW, Satoh H. 1984. Strain and sex differences in chloroform-induced nephrotoxicity Different rates of metabolism of chloroform to phosgene by the mouse kidney. Drug Metab Dispos 12 304-308. 

The dose and frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors and nongenetic variables, such as age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows summarizes the most important of these variables. 

Merrick BA, Johnson KL, Kester KA, et al. 1983. Species and sex differences in selenium inhibition of hepatic drug metabolism in rodents. Drug Chem Toxicol 6 329-340. 

Although some sex-specific differences have been observed, the mechanism by which this occurs is unknown. These differences could be a result of differences in sex steroid levels as seen with the rat, but proof in humans is lacking. Basically, because of the confounding effects of age, diet, and physiological factors, interpretation of the sex-dependent differences in drug pharmacokinetics in humans is very complex and the role of metabolism remains to be clarified. 

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