While numerous studies have evaluated the effect of oral contraceptives and postmenopausal hormone replacement on drug clearance, many were flawed by poor study design. Table 21.1 lists studies that were of crossover or sequential design such that each subject was evaluated in the contraceptive phase and placebo phase. These study designs minimize the effect of interindividual variability. In most studies there was no effect of hormonal therapy on drug metabolism, but in some there were interactions that inhibited or increased the metabolism of concurrently administered drugs.
Higher clearance rates primarily reflect the ability of oral contraceptives to increase the activity of glucuronyltransferases. The mechanisms by which oral contraceptives decrease drug metabolism are unknown. We also do not know to what extent the estrogen or the progesterone components of oral contraceptives participate in these interactions (58). Although postmenopausal hormone replacement is becoming less prevalent, drug metabolism interactions resulting from hormone replacement therapy also warrant consideration, but few data are available (77-82).
Women use herbal and dietary supplements at higher rates than men do. This rise in use of alternative therapies places women at increased risk of significant drug interactions, specifically drug-herb and drug-nutrient interactions (83-89). For instance, St. John's wort, a popular antidepressant, contains at least seven groups of chemical compounds. These include naphthodianthrons (hypericin and pseudohy-pericin), flavonoids (quercetin, hyperoside, and rutin),
TABLE 21.1 Effects of Exogenous Sex Hormones on Drug Metabolism
Metabolic pathway Probe Estrogen
PK change parameter®
CYP1A2 Antipyrine^  Caffeine 
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