with duodenal ulcers who were treated with 1,600 mg/day cimetidine. The symptoms appeared after 4 months of treatment and regressed within a month following discontinuation of cimetidine. In another small study, cimetidine was reported to have induced breast changes and erectile dysfunction in 60% of 22 men treated with it. These adverse effects completely resolved in all cases when the men were switched from cimetidine to ranitidine. A study of the United Kingdom General Practice Research Database, which contains over 80,000 men, found that the relative risk of gynecomastia in cimetidine users was 7.2 relative to non-users. People taking a dosage of cimetidine of greater than or equal to 1,000 mg showed more than 40 times the risk of gynecomastia than non-users. The risk was highest during the period of time of 7 to 12 months after starting cimetidine. The gynecomastia associated with cimetidine is thought to be due to blockade of ARs in the breasts, which results in estrogen action unopposed by androgens in this tissue, although increased levels of estrogens due to inhibition of estrogen metabolism is another possible mechanism. Cimetidine has also been associated with oligospermia (decreased sperm count) and sexual dysfunction (e.g., decreased libido, erectile dysfunction) in men in some research, which are hormonally related similarly. In accordance with the very weak nature of its AR antagonistic activity, cimetidine has shown minimal effectiveness in the treatment of androgen-dependent conditions such as acne, hirsutism (excessive hair growth), and hyperandrogenism (high androgen levels) in women. As such, its use for such indications is not recommended. Pharmacokinetics Cimetidine is rapidly absorbed regardless of route of administration. The oral bioavailability of cimetidine is 60 to 70%. The onset of action of cimetidine when taken orally is 30 minutes, and peak levels occur within 1 to 3 hours. Cimetidine is widely distributed throughout all tissues. It is able to cross the blood–brain barrier and can produce effects in the central nervous system (e.g., headaches, dizziness, somnolence). The volume of distribution of cimetidine is 0.8 L/kg in adults and 1.2 to 2.1 L/kg in children. Its plasma protein binding is 13 to 25% and is said to be without pharmacological significance. Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material.