Abstract
Studies were conducted to determine the differences in phencyclidine (PCP) in vitro metabolism and pharmacokinetics in female and male Sprague-Dawley (SD) rats. Formation rates of five major PCP metabolites in liver microsomes were significantly higher (p < .05) in males compared with females in three different rat strains (SD, Fischer 344, and Dark Agouti). In addition, the formation rate for an irreversibly bound PCP metabolite in males was the second highest of the six metabolites measured in these studies. However, the liver microsomes from the females produced essentially no metabolite binding in any strain. To determine the in vivo consequences of these in vitro metabolism results, we determined PCP’s pharmacokinetic profile in female SD rats after a pharmacologically active i.v. dose of PCP (1 mg/kg) and then compared these data with the pharmacokinetic profile in male SD rats. The value for PCP systemic (and nonrenal) clearance was more than 45% lower (p < .05) in female rats. In addition, the terminal elimination T1/2 was significantly longer (p < .05) in the female rats (5.5 versus 3.4 h, respectively). Because the initial serum concentration, volume of distribution at steady state, and renal clearance were not significantly different between the sexes, the longer half-life was attributed directly to a decreased ability of females to metabolize the drug. Consequently, these pharmacokinetic data suggest pharmacological differences in PCP effects between female and male rats are due primarily to a decreased ability of female rats to metabolize the drug.
Footnotes
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Send reprint requests to: S. Michael Owens, Ph.D., Department of Pharmacology and Toxicology, Slot 611, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205. E-mail: owenssamuelm{at}exchange.uams.edu
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↵1 This work was supported by National Institute on Drug Abuse Grants DA 4136 and DA 7610, a Research Scientist Development Award (K02 DA 00110) to S.M.O., and a National Research Service Award to S.R.S. (F31 DA 05607).
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↵2 Current address: Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, AR 72202.
- Abbreviations:
- CYP
- cytochrome P-450
- SD
- Sprague-Dawley
- PCP
- phencyclidine
- PCHAP
- 5-[N-(1′-phenylcyclohexyl)amino]pentanoic acid
- PCHP
- 1-(1-phenylcyclohexyl)-4-hydroxypiperidine
- c-PPC
- cis-1-(1-phenyl-4-hydroxycyclohexyl)piperidine
- t-PPC
- trans-1-(1-phenyl-4-hydroxycyclohexyl)piperidlne
- t-diOH
- trans-4-(4′-hydroxypiperidino)-4-phenylcyclohexanol)
- Co
- initial serum concentration
- Clnr
- nonrenal clearance
- Clr
- renal clearance
- Cls
- systemic clearance
- T1/2λz
- terminal elimination half-life
- Vss
- volume of distribution at steady state
- λz
- terminal elimination rate constant
- AUCo∞
- area under the concentration-time curve from time 0 to infinity
- Received January 19, 1999.
- Accepted April 17, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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