caa a22 4500 477057616 CHVBK 20180405111351.0 cr unu---uuuuu 170330e19960401xx s 000 0 eng 10.1007/s002280050079 doi (NATIONALLICENCE)springer-10.1007/s002280050079 Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine [Elektronische Daten] [G. Muralidharan, J. K. Cooper, E. M. Hawes, E. D. Korchinski, K. K. Midha] Quinidine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48 h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r s = −0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (α = 0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug. Springer-Verlag Berlin Heidelberg, 1996 Key words Chlorpromazine nationallicence CYP2D6 nationallicence 7-hydroxychlorpromazine nationallicence quinidine nationallicence polymorphic metabolism nationallicence Muralidharan G. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut Cooper J. K. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut Hawes E. M. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut Korchinski E. D. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut Midha K. K. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut https://doi.org/10.1007/s002280050079 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050079 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Muralidharan G. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut NATIONALLICENCE 700 1- Cooper J. K. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut NATIONALLICENCE 700 1- Hawes E. M. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut NATIONALLICENCE 700 1- Korchinski E. D. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut NATIONALLICENCE 700 1- Midha K. K. College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada, CA aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer