Abstract
A comparative study of the plasma pharmacokinetics and tissue distribution of the d-threo enantiomers of methylphenidate (MPH), para-bromomethylphenidate (p-Br MPH), andpara-methoxymethylphenidate (p-OCH3 MPH) was conducted in rats after i.p. administration of a 37 μmol/kg dose. The plasma kinetic data was fit to a two-compartment model with absorption and lag time as well as evaluated by noncompartmental methods. All three compounds attained maximal concentration within 10 min of injection. Calculated mean residence time and elimination half-life values ford-p-Br MPH were significantly longer than those for d-MPH andd-p-OCH3 MPH, and clearance of the bromo derivative was substantially lower than the latter two compounds. Tissue distribution studies of the threed-threo enantiomers revealed thatpara-substitution of d-MPH had a profound effect on the distribution pattern of these drugs. The highest concentration of drug was found in the kidney and lung ford-MPH, lung and liver ford-p-Br MPH, and lung and brain ford-p-OCH3 MPH. The bromo derivative was found in the highest concentration in the central nervous system at 30, 120, and 180 min whereas levels ofd-MPH were twice as high asd-p-OCH3 MPH at 30 min but slightly lower than the latter at 120 min. Related studies on the lipophilicity, plasma protein binding, and resistance to plasma degradation of these compounds were also conducted. The combined data from these experiments along with the pharmacokinetics and central nervous system distribution of these drugs provide explanations for discrepancies between the in vivo and in vitro activity of these compounds described in previous work.
Footnotes
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Send reprint requests to: Dr. James M. Perel, Ph.D., Director, Clinical Pharmacology Program, E-1203 Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213-2593. E-mail: pereljm{at}msx.upmc.edu
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This work was supported in part by National Institutes of Health/National Institute of General Medical Sciences Grant 5T32GM08208.
- Abbreviations used are::
- MPH
- methylphenidate
- p-Br MPH
- para-bromomethylphenidate
- p-OCH3 MPH
- para-methoxymethylphenidate
- GC-MS
- gas chromatography-mass spectrometry
- β
- elimination constant
- MRT
- mean residence time
- AUC
- area under the concentration-time curve
- CNS
- central nervous system
- EPH
- racemic threoethylphenidate
- PFPA
- pentafluoropropionic anhydride
- MSD
- mass selective detector
- Received September 23, 1998.
- Accepted February 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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