Skip to main content
SpringerLink
Log in

A Pharmacokinetic Model to Predict the PK Interaction of L-Dopa and Benserazide in Rats

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. To study the PK interaction of L-dopa/benserazide in rats. Methods. Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltrans- ferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC.

Results. The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC.

Conclusions. Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide.

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. G. F. Wooten. Pharmacokinetics of levodopa. In C. D. Marsden and S. Faka (eds.), Movement Disorders, Butterworths, 1984 pp. 231-240.

  2. Dopamine Hydrochloride. In Martindale, The Pharmaceutical Press, London, 1999 pp. 861-862.

  3. J. G. Nutt and J. H. Fellman. Pharmacokinetics of levodopa. Clin. Neuropharmacol. 7:35-49 (1984).

    Google Scholar 

  4. J. G. Nutt. Pharmacokinetics of levodopa. In W. C. Koller (ed.), Handbook of Parkinson's Disease, Marcel Dekker Inc., New York-Basel, pp. 339-354.

  5. H. J. Doller, J. D. Connor, D. R. Lock, R. S. Sloviter, B. H. Dvorchik, and E. S. Vesell. Levodopa pharmacokinetics: Alterations after benserazide, a decarboxylase inhibitor. Drug Metab. Dispos. 6:164-168 (1978).

    Google Scholar 

  6. P. S. Leppert, M. Cortese, and J. A. Fix. The effects of carbidopa dose and time and route of administration on systemic L-dopa levels in rats. Pharm. Res. 5:587-591 (1988).

    Google Scholar 

  7. S. Rose, P. Jenner, and C. D. Marsden. Peripheral pharmacokinetic handling and metabolism of L-dopa in the rat: The effect of route of administration and carbidopa pretreatment. J. Pharm. Pharmacol. 43:325-330 (1991).

    Google Scholar 

  8. S. Rose, P. Jenner, and C. D. Marsden. The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats. Mov. Disord. 3:117-125 (1988).

    Google Scholar 

  9. E. Bredberg, H. Lennernaes, and L. K. Paalzow. A study of the pharmacokinetics of levodopa in the rat following different routes of administration. Pharm. Res. 11:549-555 (1994).

    Google Scholar 

  10. S. Sato, T. Koitabishi, and A. Koshiro. Pharmacokinetic and pharmacodynamic studies of L-dopa in rats. I. Pharmacokinetic analysis of L-dopa in rat plasma and striatum. Biol. Pharm. Bull. 17:1616-1621 (1994).

    Google Scholar 

  11. K. Iwamoto, J. Watanabe, M. Yamada, F. Atsumi, and T. Matsushita. Effect of age on gastrointestinal and hepatic first-pass effects of levodopa in rats. J. Pharm. Pharmacol. 39:421-425 (1987).

    Google Scholar 

  12. D. E. Schwartz and R. Brandt. Pharmacokinetic and metabolic studies of the decarboxylase inhibitor benserazide in animals and man. Arzneimittelforschung 28:302-307 (1978).

    Google Scholar 

  13. M. Schleimer and G. Fischer. Determination of endogenous L-dopa and 3-O-methyldopa together with carbidopa or benserazide and (2,3,4-Trihydroxybenzyl)hydrazine in human plasma using solid phase extraction and HPLC with electrochemical detection. Data on File, Hoffmann-La Roche Ltd., Basel, 1996.

    Google Scholar 

  14. M. Schleimer and G. Fischer. Determination of benserazide (Ro 04-4602) and (2,3,4-Trihydroxybenzyl)hydrazine (Ro 04-5127) in human, dog and rat plasma using HPLC with electrochemical detection. Data on File, Hoffmann-La Roche Ltd., Basel, 1996.

    Google Scholar 

  15. M. Gibaldi and D. Perrier. Method of residuals. In Pharmacokinetics, Marcel Dekker Inc., New York-Basel, 1982 pp. 433-444.

    Google Scholar 

  16. S. Riegelman and P. Collier. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J. Pharmacokinet. Biopharm. 8:509-534 (1980).

    Google Scholar 

  17. W. Burkard, K. Gey, and A. Pletscher. Inhibition of decarboxylase of aromatic amino acids by 2,3,4-trihydroxybenzylhydrazine and its seryl derivative. Arch. Biochem. Biophys. 107:187-196 (1964).

    Google Scholar 

  18. B. Davies and T. Morris. Physiological parameters in laboratory animals and humans [editorial]. Pharm. Res. 10:1093-1095 (1993).

    Google Scholar 

  19. P. T. Mearrick, G. G. Graham, and D. N. Wade. The role of the liver in the clearance of 1-dopa from plasma. J. Pharmacokinet. Biopharm. 3:13-23 (1975).

    Google Scholar 

  20. M. Schmitt, M. Schleimer, and G. Fischer. Effect of tolcapone on benserazide (Ro 04-4602) plasma levels in rats. Data on File, F. Hoffmann-La Roche Ltd., Basel, 1996.

    Google Scholar 

  21. M. Schmitt, M. Schleimer, G. Fischer, M. S. Gruyer, and P. Schrag, Benserazide exposure in rats and dogs after oral administration. Data on File, F. Hoffmann-La Roche Ltd., Basel, 1997.

    Google Scholar 

  22. L. F. Lacey, O. N. Keene, J. F. Pritchard, and A. Bye. Common noncompartmental pharmacokinetic variables: Are they normally or log-normally distributed? J. Biopharm. Stat. 7:171-178 (1997).

    Google Scholar 

  23. L. Landsberg, M. B. Berardino, and P. Silva. Metabolism of 3-H-L-dopa by the rat gut in vivo-evidence for glucuronide conjugation. Biochem. Pharmacol. 24:1167-1174 (1975).

    Google Scholar 

  24. L. Rivera Calimlim, C. A. Dujoyne, J. P. Morgan, L. Lasagna, and J. R. Bianchine. Absorption and metabolism of L-dopa by the human stomach. Eur. J. Clin. Invest. 1:313-320 (1971).

    Google Scholar 

  25. K. Sasahara, T. Nitanai, T. Habara, T. Kojima, Y. Kawahara, T. Morioka, and E. Nakajima. Dosage form design for improvement of bioavailabilily of levodopa IV: Possible causes of low bioavailability of oral levodopa in dogs. J. Pharm. Sci. 70:730-733 (1981).

    Google Scholar 

  26. G. M. Tyce. Metabolism of 3,4-dihydroxyphenylalanine by isolated perfused rat liver. Biochem. Pharmacol. 20:3447-3462 (1971).

    Google Scholar 

  27. S. Cotler, A. Holazo, H. G. Boxenbaum, and S. A. Kaplan. Influence of route of administration on physiological availability of levodopa in dogs. J. Pharm. Sci. 65:822-827 (1976).

    Google Scholar 

  28. G. M. Tyce and C. A. Owen. Administration of L-3,4-dihydroxyphenylalanine to rats after complete hepatectomy-II. Excretion of metabolites. Biochem. Pharmacol. 28:3279-3284 (1979).

    Google Scholar 

  29. H. Hinterberger and C. J. Andrews. Catecholamine metabolism during oral administration of levodopa. Arch. Neurol. 26:245-252 (1972).

    Google Scholar 

  30. W. B. Abrams, C. B. Coutinho, A. S. Leon, and H. E. Spiegel. Absorption and metabolism of levodopa. JAMA 218:1912-1914 (1971).

    Google Scholar 

  31. D. N. Wade, P. T. Mearrick, D. J. Birkett, and J. Morris. Variability of L-dopa absorption in man. Aust. NZ J. Med. 4:138-143 (1974).

    Google Scholar 

  32. G. Bartholini, I. Kuruma, and A. Pletscher. Distribution and metabolism of L-3-O-methyldopa in rats. Br. J. Pharmacol. 40:461-467 (1970).

    Google Scholar 

  33. J. Gabrielsson and D. Weiner. Discrimination between rival models. In Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications, Swedish Pharmaceutical Press, Stockholm, Sweden, 1997 pp. 307-309.

    Google Scholar 

  34. R. Ferrini and A. Glässer. In vitro decarboxylation of new phenylalanine derivatives. Biochem. Pharmacol. 13:798 (1964).

    Google Scholar 

  35. M. Rowland and T. N. Tozer. Metabolite kinetics. In Clinical Pharmacokinetics: Concepts and Applications, Lea & Febiger, Philadelphia-London, 1989 pp. 347-375.

    Google Scholar 

  36. T. Walle, T. C. Fagan, E. C. Conradi, U. K. Walle, and T. E. Gaffney. Presystemic and systemic glucuronidation of propranolol. Clin. Pharmacol. Ther. 26:167-172 (1979).

    Google Scholar 

  37. R. P. Brown, M. D. Delp, S. L. Lindstedt, L. R. Rhomberg, and R. P. Beliles. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13:407-484 (1997).

    Google Scholar 

  38. K. Sasahara, T. Nitanai, T. Habara, T. Morioka, and E. Nakajima. Dosage form design for improvement of bioavailability of levodopa II: bioavailability of marketed levodopa preparations in dogs and parkinsonian patients. J. Pharm. Sci. 69:261-265 (1980).

    Google Scholar 

  39. J. A. Romero, L. D. Lytle, L. A. Ordonez, and R. J. Wurtman. Effects of L-dopa administration of the concentrations of dopa, dopamine and norepinephrine in various rat tissues. J. Pharmacol. Exp. Ther. 184:67-72 (1973).

    Google Scholar 

  40. G. A. Lyles. Effects of L-DOPA administration upon monoamine oxidase activity in rat tissues. Life Sci. 22:603-609 (1978).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. PRNS Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland

    Susan Grange & Theodor W. Guentert

  2. Division Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Nicholas H. G. Holford

Authors
  1. Susan Grange
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas H. G. Holford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodor W. Guentert
    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

Grange, S., Holford, N.H.G. & Guentert, T.W. A Pharmacokinetic Model to Predict the PK Interaction of L-Dopa and Benserazide in Rats. Pharm Res 18, 1174–1184 (2001). https://doi.org/10.1023/A:1010935228654

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1010935228654

Search

Navigation