Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

Hepatic microsomal warfarin metabolism in warfarin-resistant and susceptible mouse strains: influence of pretreatment with cytochrome P-450 inducers.

In the present paper, the heterogeneity of hepatic cytochrome P-450 isoenzymes in the mouse has been probed, using warfarin as the substrate. Both sex and strain differences in the in vitro microsomal metabolism of warfarin have been investigated in male and female warfarin-resistant HC and warfarin-susceptible LAC-grey mouse strains. Animals were either untreated or treated with the cytochrome P-450 inducers phenobarbitone, beta-napthoflavone or clofibrate. In both sexes and strains of mice, metabolism of warfarin was stereoselective in favour of the R(+) enantiomer. However, regioselectively was different in both strains and sexes of untreated animals. After pretreatment with phenobarbitone, increases in the rate of formation of 4' and 7-hydroxy R(+) and S(-) warfarin metabolites in HC mice were observed, compared with untreated animals. In LAC-grey mice increases in 4'-, 6-, 7- and 8-hydroxy R(+) and S(-) warfarin metabolites were noted, compared with untreated animals. This data indicated that different amounts or forms of cytochrome P-450s were responsible for warfarin metabolism after phenobarbitone treatment in the two strains. Pretreatment of animals with beta-napthoflavone resulted in significant decreases in the rat of R(+) warfarin metabolism in both strains and sexes of mice indicating that the beta-naphthoflavone-inducible cytochrome P-450 isoenzymes were less active in the metabolism of warfarin, as compared to the uninduced isoenzymes. In addition, the cytochrome P-450 isoenzyme composition in the two mouse strains was different after clofibrate pretreatment, as reflected in reduced levels of some warfarin metabolites and a reduced total metabolism of warfarin, consistent with the narrow substrate specificity of clofibrate-induced cytochrome P450IVA1 for fatty acid hydroxylation. Accordingly, it is clear that both the basal and xenobiotic inducible hepatic cytochrome P-450 isoenzymes in warfarin-resistant and susceptible mice are different and therefore have implications for the in vivo disposition of warfarin.

Aspects of anticoagulant action: a review of the pharmacology, metabolism and toxicology of warfarin and congeners.

Warfarin is the most widely used anticoagulant in the treatment of thromboembolism in man. It has also been used extensively as a rodenticidal agent. Insofar as its clinical use is concerned, it is now clear that many of the drug interactions observed in patients are mediated via metabolic or pharmacokinetic factors. An understanding of the disposition of warfarin is therefore essential if one is to predict the likely response in patients undergoing anticoagulant therapy with this compound. Warfarin-resistance has been reported in both man and rodents. Understanding resistance in both man and rodents is important for effective anticoagulant therapy, and in control of resistant strains of rodents. Warfarin resistance in rat strains does not appear to have a metabolic or pharmacokinetic basis; in this species, resistance is thought to be due to differences in permeability to, or affinity for a receptor. Apart from its clinical and rodenticidal uses, warfarin is an excellent substrate for probing the heterogeneity of cytochrome P.450, since its metabolic oxidation is mediated by this mixed function oxidase. This review draws together much of the current published literature on the pharmacology, metabolism and toxicology of warfarin and related congeners.