Dostinex
By C. Grubuz. North Carolina Agricultural and Technical State University.
Moreover generic 0.5mg dostinex with visa menstrual odor symptoms, Paine et al (126) recently showed that removal of furanocoumarins from grapefruit juice abol- ished its inhibitory effect on oral felodipine clearance order dostinex 0.5mg with visa women's health clinic vero beach, establishing their importance in the interaction in vivo. Role of the Gut Mucosa in Metabolically Based Drug-Drug Interactions 493 The maximum inhibitory effect appears to require consumption of more than one glass of normal- or double-strength juice. Several studies have investigated the time it takes for the inhibitory effect of grapefruit juice to dissipate (137–140). P-gp is expressed prominently on the apical (luminal) membrane of intestinal epithelia. As discussed in Chapters 8 and 12, it can function to delay or limit the oral absorption of its substrates, depending on the relative magnitude of the secretory and diffusional clearances. Specifically, they sug- gest that P-gp-mediated cell efflux increases the probability of a drug being exposed to the biotransformation enzyme through successive cycles of absorp- tion and efflux, which increases intracellular residence time and enhances the probability that it will undergo first-pass metabolism. Interestingly, their kinetic analysis of the data indicated that the effect was mediated primarily by a disproportionate increase in the rate constant for verapamil transport from tissue into mesenteric blood, with no change in the apparent rate constant for verapamil metabolism. The authors proposed that saturation of intracellular verapamil binding as a consequence of P-gp inhibition and buildup in enterocyte concentration led to the change in verapamil transport. Why the apparent rate constant for intracellular metabolism would not also be affected is unclear if the two processes draw from the same pool of unbound substrate. However, the model employed by these authors represents a closed system and 100% metabolism will eventually occur. In other words, there is a competition between apical cycling via P-gp and absorptive loss in vivo. In addition, the cultured cell monolayer studies of Hochman and Cummins involved evaluation of the extraction process over a fixed (180 minutes) period of time. However, there is no firm evidence to date to indicate that these intestinal enzymes are involved in drug-drug interactions. For example, duodenal and jejunal microsomal intrinsic clearances for metoprolol oxidation reactions were found to be only a fraction of the hepatic intrinsic clearance (165). On the basis of the well-stirred model and assuming villous blood-flow limited absorption, the first-pass intestinal and hepatic extraction ratios for metoprolol were predicted to be 2% and 61%, respectively. Drugs that are subject to sulfonation in the human small intestine include isoproterenol, salicylamide, acetaminophen, ethinyl estradiol, terbutaline, salbutamol, minoxidil, apomorphine, and budeso- nide (168,169). Small intestine has the highest activity for all four substrates compared with the stomach and colon. In contrast, intestinal sulfonation rate of 2-naphthol and dihydroepiandrosterone were one- half and one-fifth that of human liver, respectively. For example, first-pass sulfonation of isoproterenol in the dog can be reduced by coadministration of competitive substrates, sali- cylamide (173) and ascorbic acid (174). Also, both oral acetaminophen (175) and ascorbate (176) administration increase the bioavailability of ethinyl estra- diol through an inhibition of sulfotransferase activity. The effects of acetaminophen and ascorbate, both given in gram doses, are attributed to a reduction in first-pass intestinal ethinyl estradiol sulfonation, via depletion of the mucosal sulfate pool. Microsomes isolated from human intestine display appreciable glucur- onidation activity toward several drugs, including estradiol and 17b-estradiol, ethinyl estradiol (42,189), acetaminophen, propofol (190), amitriptyline, desipramine, imipramine, ibuprofen (12,191), raloxifene (192), resveratrol (193), ezetimibe (183), and troglitazone (194). However, the quantitative importance of this process compared with hepatic extraction remains to be elucidated. The best example is perhaps the clinically observed interaction between mycophenolate mofetil and tacrolimus. Tacrolimus is reportedly a good inhibitor of mycophenolic acid conjugation, both in vitro (199) and in vivo (200). Epidemiological evidence suggests that oral contraceptive failures are associated with the use of oral antibiotics. Case reports have suggested that some women have significantly reduced concen- trations of ethinyl estradiol when taken in combination with tetracyclines and penicillin derivatives (202). It is likely that the interaction, if it exists, occurs only in selected individuals who are poor metabolizers for the nonconjugative pathways (e. In contrast, the role of other intestinal drug-metabolizing enzymes in drug interactions remains speculative or controversial. Future progress in this area will require a concerted effort in developing appropriate in vitro cellular systems and conducting rigorous human studies to elucidate in vivo function and regulation of intestinal drug- metabolizing enzymes.
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