The effect of cimetidine on cyclophosphamide metabolism in rabbits |
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Authors: | Lowell B Anthony Qi-cai Long Robert F Struck Kenneth R Hande |
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Institution: | (1) Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee;(2) Nashville Veterans Administration Medical Center, Nashville, Tennessee;(3) Southern Research Institute, Birmingham, Alabama;(4) 1956 Vanderbilt Clinic, 37232-5536 Nashville, TN |
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Abstract: | Summary Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 Ci 3H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3±7.3 to 33.5±9.5 min (mean ± SD;P=0.036) but did not significantly alter the AUC0–8 h for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC0–8 h for 4-hydroxycyclophosphamide (189.4±77 vs 364.6±126.7 mol min/l–1;P=0.016) as compared with control values. A higher AUC0–8 h value for phosphoramide mustard (53.7±69.2 vs 95.7±34.7 mol min/l–1) was also observed after cimetidine dosing but the difference was not significant (P=0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.Supported in part by the Department of Veteran Affairs and grant CA-49186 from the National Institutes of Health (NIH)Department of Clinical Pharmacology, Sun Yat-sen University of Medical Sciences, Guangzhou, People's Republic of China |
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