This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The role of specific P450 isoforms in the metabolism and clearance of drugs can be identified using in vivo probes. Probes, which are selective inhibitors of a certain P450 isoform, are used to determine the effect of enzyme inhibition (or in rare cases, induction) on the disposition of the particular drug under investigation. If altering the activity of a specific P450 alters the disposition f the drug, then that P450 is said to be involved on the disposition of that drug. In vivo probes have been developed for many of the P450s. Ticlopidine, a drug that inhibits platelet aggregation and has been used clinically for several years for the prevention of atherothrombotic events, was recently identified as a selective inhibitor of human CYP2B6 activity in vitro and in vivo. The value of a probe depends upon its selectivity for a single P450. Compounds which inhibit CYP2B6 can sometimes inhibit CYP3A4. Although ticlopidine is selective for CYP2B6 in vitro, its activity on CYP3A in vivo is unknown. The purpose of this investigation is to determine the effect of ticlopidine on CYP3A activity in humans in vivo. This will be a 2-session crossover study in healthy volunteers, to determine the effect of ticlopidine on the clearance of alfentanil, which reflects the activity of CAP3A.
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