Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Nielsen, Flemming; Rosholm, Jens-Ulrik; Brøsen, Kim

doi:10.1007/bf00194341

Cited by 12 publications

(6 citation statements)

References 15 publications

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“…Although this observation is based on very few samples and thus not conclusive, it suggests that there may be a relationship between the CYP2D6 genotype and the metabolizm of quinidine. Earlier studies have indicated that although quinidine is a potent inhibitor of CYP2D6 [11–15], it is not a substrate of this enzyme [11, 30–34]. These results are, however, based on data using higher quinidine doses and concentrations than those used in the present study.…”

Section: Discussioncontrasting

confidence: 68%

Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

Dalén

Dahl

Andersson

et al. 2000

Brit J Clinical Pharma

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Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. Conclusions A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of 'treatment resistance' caused by ultrarapid metabolism.

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Section: Discussioncontrasting

confidence: 68%

Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

Dalén

Dahl

Andersson

et al. 2000

Brit J Clinical Pharma

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“…Quinidine markedly inhibited the O-demethylation of codeine in this in vitro system. This is not surprising since quinidine is a known inhibitor of CYP2D6 (Brinn et al 1986) although this enzyme is not important for the oxidation of quinidine (Nielsen et al 1995). However, although quinidine has been shown to be a substrate of CYP3A, the inhibition of N-demethylation of codeine was much weaker than the inhibition of O-demethylation of codeine by quinidine, suggesting a lower affinity of quinidine for CYP3A than CYP2D6.…”

Section: Discussionmentioning

confidence: 89%

Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes

Qy¹,

Säwe²

1997

European Journal of Clinical Pharmacology

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“…This study is one of a series of systematic interaction studies, which address the specificity of quinidine for the CYP3A4 enzyme in vivo , as high substrate specificity is obviously an essential feature of any biomarker reaction. Previously a role for CYP2D6 in the oxidation of quinidine has been excluded [ 9] and a major role for the CYP1A2 and CYP2C19 enzymes seems unlikely [ 10]. The CYP2C9 enzyme is involved in the oxidation of most nonsteroid anti‐inflammatory drugs and tolbutamide.…”

Section: Introductionmentioning

confidence: 99%

“…and a sample (10 ml) was frozen at −20°C until analysis. Blood glucose was measured after 6 h. On study day 2 Previously a role for CYP2D6 in the oxidation of quinidine has been excluded [9] and a major role for the all of the volunteers took 100 mg of sparteine sulphate (Depasan, Giulini Pharma GMBH, Germany), 100 mg CYP1A2 and CYP2C19 enzymes seems unlikely [10]. The CYP2C9 enzyme is involved in the oxidation of of mephenytoin (Mesantoin, Sandoz Pharmaceuticals Corporation, USA) and 200 mg of caffeine (Koffein most nonsteroid anti-inflammatory drugs and tolbutamide.…”

mentioning

confidence: 99%

Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine

Damkier

Hansen

Brøsen

1999

Brit J Clinical Pharma

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AimsIn vitro studies suggest that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine. Methods An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied. Results Concomitant administration of diclofenac reduced the partial clearance of quinidine by N-oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram did not alter any of the pharmacokinetic parameters of quinidine. Concomitant administration of itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxylation and partial clearance by N-oxidation by 61, 84 and 73%, respectively. The renal clerance was reduced by 60% and the elimination half-life increased by 35%. Concomitant administration of grapefruit juice reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 15, 19 and 27%, respectively. The elimination half-life of quinidine was increased by 19%. The caffeine metabolic index was reduced by 25%. Concomitant administration of erythromycin reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 34, 50 and 33%, respectively. C max was increased by 39%. Conclusions The results confirm an important role for CYP3A4 in the oxidation of quinidine in vivo, and this applies particularly to the formation of 3-hydroxyquinidine. While a minor contribution of CYP2C9 to the N-oxidation of quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzymes in the oxidation of quinidine in vivo is unlikely.

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Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Cited by 12 publications

References 15 publications

Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes

Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine

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