Reviews on drug metabolism and drug interactions最新文献

Cardiovascular diseases, osteoporosis-related hip fractures, and various cancers of the colon, prostate, uterus, and breast are remarkably less prevalent in Asia than in other industrialized countries. It is believed that the large consumption of soy products in Asian countries is contributory to the reduction of these chronic disorders. Genistein is a major isoflavone found in most soy products and plays an important role in the promotion of human health. Extensive epidemiological, in vitro, and animal studies have been performed, and most studies indicate that genistein has beneficial effects on a multitude of human disorders, including cancers, cardiovascular diseases, osteoporosis, and postmenopausal symptoms. To date, there is an abundance of promising studies supporting genistein's potential uses, but further research is still needed to validate its preventative and therapeutic efficacy. In addition, the adverse effects of genistein have drawn public attention. More studies are required to assess the potential detrimental effect of genistein, and a benefit-risk ratio should be considered before future clinical studies are performed.

Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

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.