Our objectives are to devise sensitive and specific methods of analyses in biological fluids and to delineate pharmacokinetic parameters from the time course of absorption, distribution, metabolism and excretion of selected drugs that are implicated in abuse, using the dog as the basic animal model. Pharmacokinetic studies after intravenous and oral administration of various drugs to be studied include morphine, codeine, buprenorphine, heroin and selected narcotic antagonists, phencyclidine, developed further to monitor the drugs and their metabolites in blood, urine, CSF and bile to establish precise pharmacokinetic models and quantify disposition. Particularly they will also be applied to evaluate the dose dependencies of oral absorption of morphinans and challenge the presumptions of saturable first pass effects that elevate bioavailability. The effects of simultaneous and/or sequential administration of morphine and an antagonist on each other's pharmacokinetics and disposition will be determined. These analytical methods of high sensitivity are needed in forensic medicine and will include applications of on-line HPLC post-column ion-pair extraction with UV detection of the counter-ion of normally low UV absorbing agents, electrochemical and fluorometry detection of compounds, etc. Protein binding and erythrocyte partition of these compounds will be determined by uniquely developed methods. Physicochemical parameters and rate-pH profiles of these compounds, their interconversions and degradations will be evaluated. Such studies are vital to understand and map in vivo transformations. The major routes of metabolism and disposition of methadone, buprenorphine and phencyclidine, of which there is present indecision, will be determined. Long term goals are to develop procedures and models to serve as the basis for the eventual evaluation of the pharmacokinetics of these compounds in humans, to correlate psychic and pharmacodynamic effects with the time courses of the drugs and their metabolites and to define the mode of action of antagonists. Challenging of the structure-activity relations among morphinana could result in predictive design where activity in defined by pharmacokinetic parameters such as cleavance, volumes, half-lives, etc.
