The objective of this work is to determine the importance of the human debrisoquin oxidation drug polymorphism with respect drug abuse and dependence. About 10% of the non-Oriental Caucasian population of North America lacks the cytochrome P450dbl responsible for the metabolism of several known drugs of abuse or their isomers (e.g. codeine, paramethoxyamphetamine, dextromethorphan [DM]) and is potently inhibited by other psychoactive drugs (e.g. d-propoxyphene, haloperidol, tripelennamine) and non-psychoactive drugs (e.g. quinidine). An impaired ability to metabolize active to inactive drug or failure to produce a more active metabolite will, depending on each specific drug, be associated with an increased abuse liability or decreased abuse liability, e.g. codeine conversion to morphine is markedly decreased in DM poor metabolizers (PM). We plan to: identify drugs of abuse that are substrates for and inhibitors of cytochrome P450dbl In human and non-human primate liver microsomes; determine the functional consequence of and factors modulating (e.g. inhibitors) of metabolism of drugs of abuse by monkey and human brain regions (e.g. striatum, n. accumbens) using dextromethorphan and codeine as substrates. The rank order and potency of inhibitor patterns will be determined. The functional importance of such metabolism will be established with codeine in which the binding of the high affinity metabolite to morphine u receptor will be determined. Three human studies are planned: 1) Over a three year period four groups, each of 240 well characterized males or females meeting DSM-IlIr criteria for each of cocaine or alcohol, codeine and congener, and tobacco dependence will be phenotyped with dextromethorphan and the patterns compared to a non-drug using group. 2) Three singlegraded doses of codeine will be administered orally to 10 drug-naive extensive metabolizers; 10 individuals expressing a liking for codeine and 10 'drug-naive' poor metabolizers of DM with and without quinidine (50 mg bid x 4 days) pre-treatment in a randomized single-blind placebo-controlled study to assess codeine effects and abuse liability using measures of subjective effects, e.g. ARCI scales, liking and physiologic effects. 3) In 12 extensive metabolizing normal volunteers dextromethorphan 60 mg will be administered by i.v. (infusion) and p.o. with and without quinidine pre-treatment. The detailed pharmacokinetics of dextromethorphan a prototypic drug for 0demethylation and opioid metabolism will be determined. These studies will: identify some drugs of abuse for which the dbl deficiency or inhibitors modify factors believed relevant to abuse liability; determine the ability of the brain to metabolize drugs by this mechanism; establish the clinical importance of this deficiency for one drug; possibly identify ways in which individuals at risk to abuse to particular drugs can be identified (e.g. phenotype); result in specific testing pertinent to regulatory or scheduling decisions (e.g. phenotyping); identify prospectively hazardous drug combinations/interactions; form the basis for future studies of self-administration or drug discrimination by monkeys, and result in new therapeutic strategies to prevent or treat drug abuse.
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