The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits

Abstract

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a 14C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone = 1.44 +/- 0.88 microM.h/ml vs 4.49 +/- 2.35 microM.hr/ml for doxorubicin given with high-dose ranitidine; P = 0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. 14C-Aminopyrine half-life was altered by a ranitidine dose of 25 mg/kg (aminopyrine half-life after placebo control = 97 +/- 6 min as against aminopyrine half-life after ranitidine = 121 +/- 7 min; mean +/- SEM; P less than 0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.

The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells

“…In the current study we used concentrations of Dox that were comparable to its plasma levels in animals after the injection of this agent [56], and did not detect apoptotic or necrotic endothelial cell death markers (data not shown). Our earlier studies with Dox showed that it is avidly and rapidly taken up by the cultured cells [57].…”

Ranitidine treatment and cortisol metabolism in man

“…Ranitidine, a more potent Hz-receptor antagonist, has a to-fold lower binding affmity for cytochrome P-450 (23). However, some reports suggest that ranitidine also affects the hepatic elimination of certain drugs (6)(7)(8)(24)(25)(26)(27).…”

“…While most reports indicate no effect on hepatic microsomal enzyme activity (2)(3)(4)(5), some papers suggest that an inhibition may occur after raoitidine treatment (6)(7)(8).…”

Pharmacokinetic Drug Interactions with Anticancer Drugs

“…The effect of both cimetidine (Brenner et al 1986) and ranitidine (Harris et al 1988) on the pharmacokinetics of doxorubicin in rabbits was studied because the drugs are known to inhibit cytochrome P450 to varying degrees.…”