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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA000743-15
Application #
3206816
Study Section
(DABB)
Project Start
1973-12-01
Project End
1989-05-31
Budget Start
1987-12-01
Budget End
1989-05-31
Support Year
15
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Pharmacy
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Hughes, John R; Pillitteri, Janine L; Callas, Peter W et al. (2004) Misuse of and dependence on over-the-counter nicotine gum in a volunteer sample. Nicotine Tob Res 6:79-84
Garrett, E R; Seyda, K; Marroum, P (1991) High performance liquid chromatographic assays of the illicit designer drug ""Ecstasy"", a modified amphetamine, with applications to stability, partitioning and plasma protein binding. Acta Pharm Nord 3:9-14
Garrett, E R; Chandran, V R (1990) Pharmacokinetics of morphine and its surrogates. X: Analyses and pharmacokinetics of buprenorphine in dogs. Biopharm Drug Dispos 11:311-50
Langguth, P; Khan, P J; Garrett, E R (1990) Pharmacokinetics of morphine and its surrogates. XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog. Biopharm Drug Dispos 11:419-44
Garrett, E R; Chandran, V R (1989) Pharmacokinetics of morphine and its surrogates. IX: Discrepancies among infused buprenorphine plasma concentrations sampled from different veins. J Pharm Sci 78:644-7
Garrett, E R; Shyu, W C; Ulubelen, A (1986) Pharmacokinetics of morphine and its surrogates. VIII: Naloxone and naloxone conjugate pharmacokinetics in dogs as a function of dose and as affected by simultaneously administered morphine. J Pharm Sci 75:1127-36
Garrett, E R; Derendorf, H; Mattha, A G (1985) Pharmacokinetics of morphine and its surrogates. VII: High-performance liquid chromatographic analyses and pharmacokinetics of methadone and its derived metabolites in dogs. J Pharm Sci 74:1203-14
Garrett, E R; el-Koussi A el-D (1985) Pharmacokinetics of morphine and its surrogates V: Naltrexone and naltrexone conjugate pharmacokinetics in the dog as a function of dose. J Pharm Sci 74:50-6
Garrett, E R; Chandran, V R (1985) Pharmacokinetics of morphine and its surrogates VI: Bioanalysis, solvolysis kinetics, solubility, pK'a values, and protein binding of buprenorphine. J Pharm Sci 74:515-24