Skip to main content
SpringerLink
Log in

Enantioselective Pharmacokinetics of dl-threo-Methylphenidate in Humans

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

A definitive enantioselective pharmacokinetic evaluation of dl-threo-methylphenidate (MPH) was carried out in 11 healthy volunteers, all of whom received, in a randomized crossover design, three oral administrations of MPH: immediate release (IR), slow release (SR), and SR chewed before swallowing (CH). In addition, all subjects received MPH intravenously (IV) on a separate occasion. Both plasma and urine samples were collected for up to 16 hr after each drug administration. Significant enantioselective differences were found in pharmacokinetic parameters such as CL, MRT, Vdss, AUC0 ∞, and t1/2. A profound distortion of the enantiomeric ratio for MPH (d ≫ 1) was evident in all plasma samples harvested after oral administration. After IV MPH, however, there was no significant distortion in the plasma d/1 ratio until 1.5 hr after dosing, whereafter there was a divergence of the plasma levels of the enantiomers. After oral administration of dl-MPH, the absolute bioavailability (F) of d-MPH was 0.23 and that of l-MPH was 0.05. There were no significant differences in renal clearance for d- or l-MPH after oral or IV administration, although the fraction of the dose excreted unchanged in the urine was significantly greater after IV MPH. These data suggest that enantioselective differences in the pharmacokinetics of oral MPH are the result of enantioselectivity in presystemic metabolism rather than in renal excretion, such that l-MPH is preferentially converted into l-ritalinic acid. Finally, it was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. E. J. Ariens. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur. J. Clin. Pharmacol. 26:663–668 (1984).

    Google Scholar 

  2. J. W. Hubbard, D. Ganes, H. K. Lim, and K. K. Midha. Chiral pharmacology and its consequences for therapeutic monitoring. Clin. Biochem. 19:107–112 (1986).

    Google Scholar 

  3. J. Caldwell, S. M. Winter, and A. J. Hutt. The pharmacological and toxicological significance of the stereochemistry of drug disposition. Xenobiotica 18:59–70 (1988).

    Google Scholar 

  4. D. E. Drayer. Problems in therapeutic drug monitoring: The dilemma of enantiomeric drugs in man. Ther. Drug Monit. 10:1–7 (1988).

    Google Scholar 

  5. K. Williams and E. Lee. Importance of drug enantiomers in clinical pharmacology. Drugs 30:333–354 (1985).

    Google Scholar 

  6. E. J. Ariens. Stereochemistry and Biological Activity of Drugs, Blackwell Scientific, Oxford, London, 1983.

    Google Scholar 

  7. V. I. Douglas, R. G. Barr, M. E. O'Neill, and B. G. Britton. Short-term effects of methylphenidate on the cognitive, learning and academic performance of children with attention deficit disorder in the laboratory and the classroom. J. Child Psychol. Psychiat. 27:191–211 (1986).

    Google Scholar 

  8. D. Whitehouse, U. Shah, and F. B. Palmer. Comparison of sustained release and standard methylphenidate in the treatment of minimal brain dysfunction. J. Clin. Psychiat. 41:282–285 (1980).

    Google Scholar 

  9. B. A. Faraj, Z. H. Israili, J. M. Perel, M. L. Jenkins, S. G. Holtzman, S. A. Cucinell, and P. G. Dayton. Metabolism and disposition of methylphenidate-14C: Studies in man and animals. J. Pharmacol. Exp. Ther. 191:535–547 (1974).

    Google Scholar 

  10. B. A. Faraj and M. L. Jenkins. Two new metabolites of methylphenidate. Pharmacologist 15:155 (1973).

    Google Scholar 

  11. H. Egger, F. Bartlett, R. Dreyfuss, and J. Karliner. Metabolism of methylphenidate in dog and rat. Drug Metab. Dispos. 9:415–423 (1981).

    Google Scholar 

  12. R. M. Ferris, F. L. M. Tang, and R. A. Maxwell. A comparison of the capacities of isomers of amphetamine, deoxypipradol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta. J. Pharmacol. Exp. Ther. 181:407–416 (1972).

    Google Scholar 

  13. R. M. Ferris and F. L. M. Tang. Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradol on the uptake of 1-[3H]-norepinephrine and [3H]-dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus. J. Pharmacol. Exp. Ther. 210:422–428 (1979).

    Google Scholar 

  14. R. Rometsch. U.S. Patent 2,838,519 (1958).

  15. R. A. Maxwell, E. Chaplin, S. Batmanglidj Eckhardt, J. R. Soares, and G. Hite. Conformational similarities between molecular models of phenethylamine and of potent inhibitors of the uptake of tritiated norepinephrine by adrenergic nerves in rabbit aorta. J. Pharmacol. Exp. Ther. 241:152–158 (1970).

    Google Scholar 

  16. K. S. Patrick, R. W. Caldwell, R. M. Ferris, and G. R. Breese. Pharmacology of the enantiomers of threo-methylphenidate. J. Pharmacol. Exp. Ther. 241:152–158 (1987).

    Google Scholar 

  17. N. R. Srinivas, D. Quinn, J. W. Hubbard, and K. K. Midha. Stereoselective disposition of methylphenidate in children with attention-deficit disorder. J. Pharmacol. Exp. Ther. 241:300–306 (1987).

    Google Scholar 

  18. H. K. Lim, J. W. Hubbard, and K. K. Midha. Development of enantioselective gas chromatographic quantitation assay for dlthreo-methylphenidate in biological fluids. J. Chromatogr. 378:109–123 (1986).

    Google Scholar 

  19. T. Aoyoma, H. Kotaki, and Y. Saitoh. Gas chromatographicmass spectrometric analysis of threo-methylphenidate enantiomers in plasma. J. Chromatogr. 494:420–423 (1989).

    Google Scholar 

  20. T. Aoyoma, H. Kotaki, Y. Honda, and F. Nakagawa. Kinetic analysis of enantiomers of threo-methylphenidate and its metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method. J. Pharm. Sci. 79:465–469 (1990).

    Google Scholar 

  21. J. W. Hubbard, N. R. Srinivas, D. Quinn, and K. K. Midha. Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactivity disorder. J. Pharm. Sci. 78:944–947 (1989).

    Google Scholar 

  22. N. R. Srinivas, J. W. Hubbard, and K. K. Midha. Enantioselective gas chromatographic assay with electron capture detection for dl-ritalinic acid in plasma. J. Chromatogr. 530:327–336 (1990).

    Google Scholar 

  23. R. B. Rosse and W. L. Licamele. Slow-release methylphenidate: Problems when children chew tablets. J. Clin. Psychiat. 48:525 (1984).

    Google Scholar 

  24. M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications, Lea and Febiger, Philadelphia, 1989.

    Google Scholar 

  25. M. D. Rapport, G. J. Du Paul, G. Stoner, B. K. Birmingham, and G. Masse. Attention deficit disorder with hyperactivity: Differential effects of methylphenidate on impulsivity. Pediatrics 76:938–943 (1985).

    CAS  PubMed  Google Scholar 

  26. M. M. Seberchts, S. E. Shaywitz, B. A. Shaywitz, P. Jatlow, G. M. Anderson, and D. J. Cohen. Components of attention, methylphenidate dosage and blood levels in children with attention deficit disorder. Pediatrics 77:222–228 (1986).

    Google Scholar 

  27. S. S. Kupietz, B. G. Winsberg, E. Richardson, S. Maitinsky, and N. Mendell. Effects of methylphenidate dosage in hyperactive reading-disabled children. I. Behaviour and cognitive performance effects. J. Am. Acad. Child Adolesc. Psychiat. 27:70–77 (1988).

    Google Scholar 

  28. B. G. Winsberg, S. S. Kupeitz, J. Sverd, B. L. Hungund, and N. L. Young. Methylphenidate and dose plasma concentrations and behavioural response in children. Psychopharmacology 76:329–332 (1982).

    Google Scholar 

  29. W. Wargin, K. Patrick, C. Kilts, C. T. Gualtieri, K. Ellington, R. A. Mueller, G. Kraemer, and G. R. Breese. Pharmacokinetics of methylphenidate in man, rat and monkey. J. Pharmacol. Exp. Ther. 226:382–386 (1983).

    Google Scholar 

  30. S. A. Shaywitz, R. D. Hunt, P. Jatlow, D. J. Cohen, G. Young, N. Pierce, G. M. Anderson, and B. A. Shaywitz. Psychopharmacology of attention deficit disorder: Pharmacokinetic, neuroendocrine and behavioural measures following acute and chronic treatment with methylphenidate. Pediatrics 69:688–694 (1982).

    Google Scholar 

  31. N. R. Srinivas, J. W. Hubbard, E. D. Korchinski, and K. K. Midha. Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans. J. Pharm. Sci. 81:747–749 (1992).

    Google Scholar 

  32. K. S. Patrick, K. R. Ellington, and G. R. Breese. Distribution of methylphenidate and p-hydroxymethylphenidate in rats. J. Pharmacol. Exp. Ther. 231:61–65 (1984).

    Google Scholar 

  33. J. Gal, B. J. Hodshon, C. Pintauro, B. L. Flamm, and A. K. Cho. Pharmacokinetics of methylphenidate in the rat using single-ion monitoring GLC-mass spectrometry. J. Pharm. Sci. 66:866–869 (1977).

    Google Scholar 

  34. B. L. Hungund, J. M. Perel, M. J. Hurwic, J. Sverd, and B. G. Winsberg. Pharmacokinetics of methylphenidate in hyperkinetic children. Br. J. Clin. Pharm. 8:571–576 (1979).

    Google Scholar 

  35. K. S. Patrick, A. B. Straughn, E. J. Jarvi, G. R. Breese, and M. Meyer. The absorption of sustained-release methylphenidate formulations compared to an immediate-release formulation. Biopharm. Drug Dispos. 10:165–171 (1989).

    Google Scholar 

  36. Y. M. Chan, J. M. Swanson, S. S. Soldin, J. J. Thiessen, S. M. Macleod, and W. Logan. Methylphenidate hydrochloride given with or before breakfast. II. Effects on plasma concentrations of methylphenidate and ritalinic acid. Pediatrics 72:56–59 (1983).

    Google Scholar 

  37. B. Birmaher, L. L. Greenhill, T. D. Cooper, J. Fried, and B. Naminski. Sustained release methylphenidate: Pharmacokinetic studies in ADDH males. J. Am. Acad. Child Adolesc. Psychiat. 28:768–772 (1989).

    Google Scholar 

Download references

Author information

Author notes

  1. Nuggehally R. Srinivas

    Present address: Pharmaceutical Research Division, Bristol Myers Squibb Company, P.O. Box 4755, Syracuse, New York, 13221-4775

Authors and Affiliations

  1. Colleges of Pharmacy and Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 0W0, Canada

    Nuggehally R. Srinivas, John W. Hubbard, Elarien D. Korchinski & Kamal K. Midha

Authors
  1. Nuggehally R. Srinivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John W. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elarien D. Korchinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kamal K. Midha
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Srinivas, N.R., Hubbard, J.W., Korchinski, E.D. et al. Enantioselective Pharmacokinetics of dl-threo-Methylphenidate in Humans. Pharm Res 10, 14–21 (1993). https://doi.org/10.1023/A:1018956526016

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018956526016

Search

Navigation