The influence of cimetidine versus ranitidine on doxepin pharmacokinetics

Abstract

The effect of cimetidine and ranitidine on doxepin pharmacokinetics was studied in 6 healthy volunteers. Each subject completed 3 study phases: Treatment A, 9 consecutive doses of 50 mg doxepin (once daily); Treatment B, same as Treatment A but co-administration of cimetidine 600 mg b.i.d. starting after the sixth doxepin dose and continuing until approximately 2 days following discontinuation of doxepin administration; Treatment C, identical to Treatment B but with ranitidine 150 mg b.i.d. instead of cimetidine. Unlike ranitidine, cimetidine co-administration resulted in a significant increase in steady state plasma levels of doxepin (4.7, 9.0 and 4.5 ng/ml during Treatments A, B and C respectively) but not desmethyldoxepin (4.1, 4.6 and 4.2 ng/ml during Treatments A, B and C respectively). Elimination half-lives of doxepin and desmethyldoxepin were prolonged by cimetidine co-administration (19.6 and 26.2 h respectively), but remained unchanged during the ranitidine treatment phase (13.3 and 18.4 h) as compared to the control phase i.e. Treatment A (13.2 and 19.0 h). These results show that cimetidine, unlike ranitidine, significantly inhibits the biotransformation of doxepin. This data has clinical implications when the co-administration of tricylic antidepressants and H2-receptor antagonists are indicated.

Side Effects of Ranitidine

“…No significant changes in imipramine, amitriptyline or doxepin pharmacokinetics were shown in studies with healthy volunteers following ranitidine pretreatment or with simultaneous administration (Curry et al 1987;Kurowski & Reim 1986;Sutherland et al 1987;Wells et al 1986). Experimental studies performed in vitro with human liver microsomes showed that imipramine demethylation or demethyl-imipramine hydroxylation were not changed (Spina & Koike 1986).…”