Pretreatment with antineoplastic drugs for at least 1 week is known to reduce in vivo metabolic clearance of antipyrine in rats tested after 24 h of fasting and restraining. In this study hepatic metabolism of 14C-antipyrine was investigated in 9,000 g supernatants of fed, unrestrained rats pretreated with cyclophosphamide, 5-fluorouracil or methotrexate. Total antipyrine metabolites formed were measured by a radiometric assay. Apparent vmax and Km values were estimated and transformed to intrinsic (hepatic) clearance and total (body) clearance for comparison with in vivo terms of metabolic rate. Hepatic microsomal metabolism of antipyrine in control rats expressed as intrinsic clearance, 0.12 ± 0.03 ml (g liver min)^–1, and total clearance, 4.8 ± 1.2 ml (kg body wt min)^–1, was not significantly changed after antineoplastic pretreatment, indicating that the previously observed inhibitory action of these drugs on in vivo antipyrine metabolism may be modulated by factors such as fasting and stress.

The pharmacokinetics of antipyrine was investigated in individual rats pretreated with cyclophosphamide, 5‐fluorouracil and methotrexate. Before oral dosing a complete emptying of the rat stomach was obtained by 24 hours of fasting and prevention of coprophagy. Antipyrine was given intravenously via a cannula in an inguinal vein and repeated samples of blood were drawn from a cannula in an inguinal artery. Systemic availability of oral antipyrine was studied in rats given the 14C‐labelled drug intravenously and the 3H‐labelled drug orally after pretreatment with cyclophosphamide. The log plasma concentration versus time curve of antipyrine given orally showed a short absorption and distribution phase followed by a linear elimination phase. Peak antipyrine concentrations were reached 3–6 minutes after oral dosing in control rats. The rate of absorption of antipyrine was moderately decreased by methotrexate. All drugs increased the area under the curve (AUC) of antipyrine. The systemic availability of oral antipyrine after cyclophosphamide pretreatment (0.88) was not changed, but the metabolic clearance of the drug was reduced. The apparent elimination rate constant was decreased by methotrexate and the apparent volume of distribution was decreased by cyclophosphamide and 5‐fluorouracil. The results indicate that antineoplastic agents may change drug kinetics in different ways in rats.