Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man.

Brøsen, Kim; Davidsen, Flemming; Gram, Lennart

doi:10.1111/j.1365-2125.1990.tb03628.x

Cited by 20 publications

(10 citation statements)

References 21 publications

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“…In the present study, we found that renal clearance accounted for 14% in the PM and 18% in the EM (Table 1), in agreement with previous panel studies [6,7]. Somewhat surprisingly, the renal clearance was significantly lower in the PM than the EM (Table 1).…”

Section: Discussionsupporting

confidence: 82%

“…Mikus et al [6] gave 200 mg quinidine intravenously to three extensive (EM) and three poor metabolisers (PM) and did not find any significant difference between the two phenotypic groups in the total or partial clearance via 3-hydroxylation of quinidine. Brosen et al [7] found that the 3-hydroxylation clearance of quinidine was significantly lower in four PM compared to four EM after oral administration of 400 mg quinidine sulphate. Both of these studies suffered from a small number of participants and the considerable attendant risk of a type II error.…”

mentioning

confidence: 99%

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Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Nielsen

Rosholm

Brøsen

1995

Eur J Clin Pharmacol

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Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l.h-1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l.h-1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Nielsen

Rosholm

Brøsen

1995

Eur J Clin Pharmacol

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“…The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l h −1 . Assuming an average plasma quinidine concentration of 2.2 µ M between 1 and 13 h after quinidine dose [38] (corresponding to 0–12 h post DEX dose) and 86 ± 6% protein binding [39], the in vivo Ki of quinidine was estimated to be 0.017 (± 0.002 SD) µM based on unbound drug.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the intrinsic clearance of DEX was decreased by (1 + [I]/Ki)‐fold in the presence of quinidine and the [I]/Ki ratio, as a single model parameter, represented the potency of quinidine inhibition in each individual. The calculated [I]/Ki ratio was used to estimate the in vivo Ki knowing the average 1–13‐h post‐dose plasma concentration of quinidine from in vivo studies [38] and its unbound fraction in plasma [39].…”

Section: Methodsmentioning

confidence: 99%

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition

Moghadamnia

Rostami‐Hodjegan

Abdul-Manap

et al. 2003

Brit J Clinical Pharma

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Aims To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX. Methods Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydrobromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms. Results The best-fit PK model assumed two-and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l h -1 , which overlapped with that extrapolated from in vitro data (12-261 l h -1 ) and showed similar variation (26-vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 m M. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (k e0 = 0.07 h -1 ). Conclusions Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.

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“…Quinidine is a comparatively weak P‐gp inhibitor, and plasma quinidine concentrations may have been inadequate to inhibit brain P‐gp activity [56]. The I C 50 for quinidine inhibition of P‐gp was 2–34 µ m in vitro [29, 57, 58], whereas oral quinidine (600 mg) gives peak plasma concentrations of only about 6 µ m [59]. Thus systemic quinidine concentrations may not have been sufficiently high to inhibit brain P‐gp activity and P‐gp mediated methadone transport.…”

Section: Discussionmentioning

confidence: 99%

The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

Kharasch

Hoffer²,

Whittington³

2004

Brit J Clinical Pharma

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AimsThere is considerable unexplained interindividual variability in the methadone doseeffect relationship. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P-gp substrate in vitro , and P-gp affects methadone analgesia in animals. However the role of P-gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe. MethodsTwo randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo. ResultsQuinidine did not alter the effects of intravenous methadone. Miosis t max (0.3 ± 0.3 vs 0.3 ± 0.2 h ( -0.17, 0.22)), peak (5.3 ± 0.8 vs 5.1 ± 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 ± 5.7 vs 26.8 ± 7.1 mm h ( -6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased ( P < 0.05) plasma methadone concentrations during the absorptive phase, decreased t max (2.4 ± 0.7 vs 1.6 ± 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 ± 1.5 vs 4.3 ± 1.6 mm ( -1.96, -0.19)) after oral methadone. The C max (55.6 ± 10.3 vs 59.4 ± 14.1 ng ml -1 ( -8.5, 0.65)) and AUC of methadone (298 ± 46 vs 316 ± 74 ng ml -1 h ( -54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment ( k e0 ) (2.6 ± 2.6 vs 2.5 ± 1.4 h -1 ( -3.5, 4.2)). ConclusionsQuinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P-gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp does not appear to be a determinant of the access of methadone to the brain. Methadone and P-glycoproteinBr J Clin Pharmacol 57 :5 601

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Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man.

Cited by 20 publications

References 21 publications

Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition

The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

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