Summary
In order to determine whether the metabolism of the antiarrhythmic drug N-propylajmaline is under the same genetic control as sparteine metabolism, the pharmacokinetics of this antiarrhythmic drug were studied in a group of six extensive and four poor metabolizers of sparteine. Pronounced differences in terminal half-life, total plasma clearance, metabolic clearance and urinary excretion of N-propylajmaline were observed between extensive and poor metabolizers. A close relationship between the total clearance and metabolic clearance of N-propylajmaline and sparteine could be demonstrated. Clinically available N-propylajmaline is a 55% to 45% mixture of thei-andn-diastereomers. The extensive metabolizers exhibited stereoselective metabolism; thei-diastereomer was preferentially metabolized. Poor metabolizers were characterized by a loss of this stereoselective metabolism. Five subjects were treated for 7 days with a daily N-propylajmaline dosage of either 60 mg or 20 mg. Since a close relationship between the clearance of N-propylajmaline and the metabolic ratio of sparteine had been observed after single dosing the metabolic ratio of sparteine was used to predict N-propylajmaline steady-state plasma concentrations during multiple dosing. Only in two extensive metabolizers with a metabolic ratio <0.4 predicted and observed, steady-state plasma concentrations were in good agreement. In the other three subjects observed steady-state plasma concentrations were appreciably higher than predicted. In these three subjects metabolic N-propylajmaline clearance decreased indicating saturation of N-propylajmaline metabolism during multiple dosing. The data indicate that N-propylajmaline metabolism is subject to a genetic polymorphism controlled by the sparteine/debrisoquine gene locus.
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Abbreviations
- Ae :
-
amount of drug excreted in urine
- AUC0 :
-
area under the curve
- CL:
-
Plasma Clearance
- CLm :
-
metabolic plasma clearance
- CL0 :
-
apparent oral plasma clearance
- CLr :
-
renal clearance
- Css :
-
steady-state plasma concentrations
- D0 :
-
oral dose
- EM:
-
extensive metabolizer
- HPLC:
-
high perform liquid chromatography
- M:
-
metabolite
- MR:
-
metabolic ratio
- NPAB:
-
N-propylajmalinum hydrogen tartrate
- PM:
-
poor metabolizer
- PVC:
-
premature ventricular contractions
- t1/2z :
-
terminal half-life
References
Bussmann WE, Müller E, Hänel HJ, Kaltenbach M (1978) Orally administered prajmalium bitartrate in acute and chronic ventricular arrhythmias. Am J Cardiol 41:577–583
Dayer P, Leemann T, Marmy A, Rosenthaler J (1985a) Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentrations and effects: Influence of genetic status on behaviour of atenolol, bopindolol and metaprolol. Eur J Clin Pharmacol 28:149–154
Dayer P, Leeman T, Gut J, Kronbach T, Küpfer A, Francis R, Meyer U (1985b) Steric configuration and polymorphic oxidation of lipophilic beta-adrenoceptor blocking agents: in vivo — in vitro correlations. Biochem Pharmacol 34:399–400
Dengler HJ, Eichelbaum M (1977) Polymorphismen und Defekte des Arzneimittelstoffwechsels als Ursache toxischer Reaktionen. Arzneim Forsch Drug Res 27:1836–1844
Eichelbaum M, Spannbrucker N, Dengler HJ (1978) A probably genetic defect of the metabolism of sparteine. In: Gorrod JW (ed) Biological oxidation of nitrogen. Elsevier/North Holland Biomedical Press 113–118
Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man — A new pharmacogenetic defect. Eur J Clin Pharmacol 16:183–187
Eichelbaum M (1982a) Defective oxidation of drugs: Kinetic and therapeutic implications. Clin Pharmacokinet 7:1–22
Eichelbaum M (1984) Polymorphic drug oxidation in humans. Fed Proc 43:98–102
Francis RJ, East PB, Larman J (1983) Kinetics and metabolism of (+), (−) and (±) bufuralol. Eur J Clin Pharmacol 23:529–533
Hausleiter HJ, Achtert G, Khan MA, Kukovetz WR, Beubler E (1982) Pharmakokinetik und Biotransformation von N-Propylajmalin-hydrogentartrat beim Menschen. Eur J Drug Metab Pharmacokinet 7:329–339
Idle JR, Smith RL (1979) Polymorphism of drug oxidation at carbon centers of drugs and their clinical signification. Drug Metab Rev 9:301–317
Idle JR, Smith RL (1984) The debrisoquine hydroxylation gene: A gene of multiple consequence. In: Lemberger L, Reidenberg MM (Hrsg) Proceedings of the Second World Conference on Clinical Pharmacology and Therapeutics. American Society for Pharmacology and Experimental Therapeutics, pp 148–164
Küpfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26:753–759
Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF (1983) Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin meta-bolizers. Clin Pharmacol Ther 34:732–737
Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1979) The polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586
Osikowska-Evers BA, Robertz GM, Dayer P, Meyer U, Eichelbaum M (1985) Kinetics of sparteine metabolism in human liver microsomes. In: Naunyn-Schmiedeberg's Arch Pharmacol R 12:329
Persson BA (1982) Assay of N-propylajmaline in blood by ion-pair liquid-liquid chromatography. J Liq Chromatogr 5:141–150
Persson BA, Karger BL (1974) High performance ion pair partition chromatography: the separation of biogenic amines and their metabolites. J Chromatgr Sci 12:521
Scherer A (1984) Isolierung (aus Ratten- und Menschenleber-9,000 × g-Überstand) und Synthese von 2 Metaboliten (Diastereomere) des Antiarrhythmicums N-Propyl-Ajmalin-Bitartrat. Inauguraldissertation der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel
Schwarzkopff B, Schilling G, Simon H (1983) Comparison of Tocainide and prajmalium-bitartrate for the treatment of ventricular arrhythmias. Arzneim Forsch Drug Res 33:153–158
Scott J, Poffenbarger PL (1979) Pharmacogenetics of tolbutamide metabolism in humans. Diabetes 28:41–51
Trompler AT, Woodcock BG, Bussmann M (1983) Pharmakokinetik und antiarrhythmische Wirkung von Prajmaliumbitartrat. Arzneim Forsch Drug Res 33:436–439
Wagner JG, Northam JI, Alway CD, Carpenter OS (1965) Blood levels of drug at the equilibrium state after multiple closing. Nature 207:1301–1302
Waring RH, Mitchell SC, Shah RR, Idle JR, Smith RL (1982) Polymorphic sulphoxidation of S-carboxymethyl-L-cysteine in man. Biochem Pharmacol 31:3151–3154
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Dedicated to Professor Dr. H.J. Dengler on the occasion of his 60th birthday
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Zekorn, C., Achtert, G., Hausleiter, H.J. et al. Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation. Klin Wochenschr 63, 1180–1186 (1985). https://doi.org/10.1007/BF01740595
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DOI: https://doi.org/10.1007/BF01740595