Summary
Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
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References
Hespe W, de Roos AM, Nauta WT (1965) Investigation into the metabolic fate of orphenadrine hydrochloride after oral administration to male rats. Arch Int Pharmacodyn 156: 180–200
Hespe W, Kafoe WF, Nauta WT (1967) Evidence for a sidechain degradation of orphenadrine hydrochloride in the rat. Biochem Pharmacol 16: 1847–1848
Roozemond RC, Hespe W, Nauta WT (1968) The concentrations of orphenadrine and its N-demethylated derivatives in rat brain, after intraperitoneal administration of orphenadrine and tofenacine. Int J Neuropharmacol 7: 293–300
Prins H, Hespe W (1968) Autoradiographic study of the distribution of radioactivity in mice after oral administration of tritiumlabeled orphenadrine hydrochloride. Arch Int Pharmacodyn 171: 47–57
Hespe W, Kafoe WF (1970) Aspects of the biliary excretion of orphenadrine and its N-demethylated derivative, tofenacine, in the rat. Eur J Pharmacol 13: 113–122
Ellison T, Snyder A, Bolger JW, Okun R (1971) Metabolism of orphenadrine citrate in man. J Pharmacol Exp Ther 176: 284–295
Ellison T (1972) Metabolic studies of3H-orphenadrine citrate in the rat, dog and Rhesus monkey. Arch Int Pharmacodyn 195: 213–230
Kahn F (1972) Ph. D. Metabolism of some antihistaminics. Thesis, University of London
Wiersinga WM, Fabius AJM, Touber JL (1977) Orphenadrine (Disipal), Serum thyroxine and Thyroid function. Acta Endocrinol 86: 522–532
Labout JJM, Thijssen CT, Hespe W (1977) Sensitive and specific gaschromatographic and extraction method for the determination of orphenadrine in human body fluids. J Chromatogr 144: 201–208
Wagner JG (1975) Fundamentals of clinical pharmacokinetics (1975). Drug Intelligence Publications, Hamilton, IL
Dye JL, Nicely VA (1971) A general purpose curve-fitting program for class and research use. J Chem Educ 48: 443–448
Perrier D, Ashley JJ, Levy G (1973) Effect of product inhibition on kinetics of drug elimination. J Pharmacokinet Biopharmacol 1: 231–242
Bast A (1981) Ph. D. Interactions of drug metabolites with hepatic cytochrome P-450. Some implications for drug metabolism. Thesis, University of Utrecht
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Labout, J.J.M., Thijssen, C.T., Keijser, G.G.J. et al. Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man. Eur J Clin Pharmacol 21, 343–350 (1982). https://doi.org/10.1007/BF00637624
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DOI: https://doi.org/10.1007/BF00637624