The long-term objective of this proposal is to determine the extent to which sex dimorphism and age contribute to the wide between-patient variability in steady-state blood levels that occurs with certain drugs, and to determine the biochemical mechanisms involved. Our working hypothesis is that estrogens and androgens exert regulatory roles (estrogens mainly inhibitory and androgens mainly stimulatory) on hepatic drug metabolism and that these effects are specific for certain enzymes. Our preliminary studies in man have shown that the clearance of propranolol, one of the most widely used cardiovascular drugs, is sensitive to both sex and age differences. In the proposed studies we will use propranolol as a model drug to evaluate the influence of sex steroid hormones on the clearances through three specific metabolic pathways (two distinct cytochrome P-450s and a glucuronosyltransferase). This will be accomplished in man in a clinical research facility, following simultaneous intravenous and oral doses of propranolol, as well as in the rat as a potential model of man and in isolated cultured rat hepatocytes. Drug and metabolites will be measured by GC/MS and stereospecific HPLC and sex steroid hormones by specific RIAs.
In Aim 1 we will examine the influence of gender, age and the normally fluctuating levels of the sex steroid hormones on the partial metabolic clearances of propranolol in young and old women and men as well as on different days of the menstrual cycle in young women.
In Aim 2 we will determine the effects of pharmacologically induced elevations of the sex steroid hormones; during estrogen therapy in postmenopausal women and after androgen administration in male volunteers.
In Aim 3 we will determine if the rat is a suitable model of man with respect to the influence of sex steroid hormone fluctuations in propranolol metabolism and answer the question whether physiological concentrations of these hormones exert direct effects on propranolol metabolism in isolated cultured rat hepatocytes. Specifically, the proposed studies will determine the contribution of gender, age and circulating sex steroid hormones to the large between-patient variability in steady-state blood levels of propranolol. More generally, these studies will establish a solid base, in man as well as in animal and cell model systems, from which mechanistic studies on the influence of sex steroid hormones on drug clearance in man can be undertaken.
