Abstract
The goal of these studies was to examine the relationship between the rate of phencyclidine (PCP) administration and PCP tissue distribution. The time course of PCP distribution in serum, brain, and testis after rapid (i.v.) and slow (s.c.) administration was studied. Brain and serum PCP concentrations after an i.v. bolus dose (1 mg/kg at 900 μg/min) were highest at 30 s and decreased biphasically, with serum concentrations decreasing 30 times faster than brain concentrations during the early phase. Consequently, the brain-to-serum PCP concentration ratio increased from 8:1 at 30 s to 14:1 at 20 min before equilibrating at a ratio of 3:1 that remained constant from 1 to 8 h. In contrast, the testis-to-serum ratio increased slowly from 1:1 to 12:1 over 4 h, and then remained constant. In a separate group of animals, an s.c. infusion of PCP (18 mg/kg/day or 3.6 μg/min) produced a brain-to-serum ratio (6:1) that remained constant throughout the 96-h infusion. Testis-to-serum ratios increased from 4:1 at 1 h to 12:1 at 8 h and then remained constant for 96 h. Steady-state infusion of a pharmacologically inactive dose (2.5 mg/kg/day) produced a brain-to-serum ratio (3:1) that was significantly lower than the ratio (6:1) after infusion of the three pharmacologically active doses (10–25 mg/kg/day). The temporary high brain PCP concentrations and the dynamic disequilibrium between brain and serum concentrations after rapid i.v. administration could provide a better understanding of the preference of the human drug abuser for rapid rates (e.g., i.v. or smoking) of drug administration.
Footnotes
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Send reprint requests to: S. Michael Owens, Ph.D., Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 611, Little Rock, AR 72205. E-mail: owenssamuelm{at}exchange.uams.edu or W. Brooks Gentry, M.D., Department of Anesthesiology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 515, Little Rock, AR 72205. E-mail: gentrywilliamb{at}exchange.uams.edu
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↵1 Current address: Joel W. Proksch, Ph.D., SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., P.O. Box 1539, UW2720, King of Prussia, PA 19406.
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This work was supported by National Institute on Drug Abuse Grants DA 07610 (to S.M.O.), Clinician/Scientist Development Award K08 DA0339 (to W.B.G.), and National Research Service Award F31 DA 05795 (to J.W.P.).
- Abbreviations used are::
- CLS
- systemic clearance
- NMDA
- N-methyl-d-aspartate
- PCP
- phencyclidine
- RIA
- radioimmunoassay
- t1/2λz
- terminal elimination half-life
- Received December 20, 1999.
- Accepted March 28, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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