potential for a large number of pharmacokinetic interactions. Cimetidine is reported to be a competitive and reversible inhibitor of several CYP enzymes, although mechanism-based (suicide) irreversible inhibition has also been identified for cimetidine's inhibition of CYP2D6. It reversibly inhibits CYP enzymes by binding directly with the complexed heme-iron of the active site via one of its imidazole ring nitrogen atoms, thereby blocking the oxidation of other drugs. Antiandrogenic and estrogenic effects Cimetidine has been found to possess weak antiandrogenic activity at high doses. It directly and competitively antagonizes the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). However, the affinity of cimetidine for the AR is very weak; in one study, it showed only 0.00084% of the affinity of the anabolic steroid metribolone (100%) for the human AR (Ki = 140 μM and 1.18 nM, respectively). In any case, at sufficiently high doses, cimetidine has demonstrated weak but significant antiandrogenic effects in animals, including antiandrogenic effects in the rat ventral prostate and mouse kidney, reductions in the weights of the male accessory glands like the prostate gland and seminal vesicles in rats, and elevated gonadotropin levels in male rats (due to reduced negative feedback on the axis by androgens). In addition to AR antagonism, cimetidine has been found to inhibit the 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased estrogen levels. The medication has also been reported to reduce testosterone biosynthesis and increase prolactin levels in individual case reports, effects which might be secondary to increased estrogen levels. At typical therapeutic levels, cimetidine has either no effect on or causes small increases in circulating testosterone concentrations in men. Any increases in testosterone levels with cimetidine have been attributed to the loss of negative feedback on the HPG axis that results due to AR antagonism. At typical clinical dosages, such as those used to treat peptic ulcer disease, the incidence of gynecomastia (breast development) with cimetidine is very low at less than 1%. In one survey of over 9,000 patients taking cimetidine, gynecomastia was the most frequent endocrine-related complaint but was reported in only 0.2% of patients. At high doses however, such as those used to treat Zollinger–Ellison syndrome, there may be a higher incidence of gynecomastia with cimetidine. In one small study, a 20% incidence of gynecomastia was observed in 25 male patients