Dose-dependent pharmacokinetics of aprindine in healthy volunteers

Kobari, Takashi; Itoh, Toshiya; Hirakawa, Toshiki; Namekawa, Hiroshi; Suzuki, T; Satoh, Takashi; Iida, Nobuko; Ohtsu, Fumio; Hayakawa, Hirokazu

doi:10.1007/bf00546721

Cited by 14 publications

(3 citation statements)

References 7 publications

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“…There was no evidence that the rate of metabolism of mexiletine was impaired or saturated at the higher doses. Thus the kinetics of mexiletine are quite different to those of aprindine (Kobari et al, 1984) and phenytoin, antiarrhythmic drugs exhibiting dose-dependent pharmacokinetics (Richens & Dunlop, 1975). There were significant differences between the plasma elimination half-lives of mexiletine for different doses but not between subjects (7.9 + 0.6 h after 300 mg and 11.3 + 1.0 h after 100 mg).…”

Section: Discussionmentioning

confidence: 89%

Dose independent pharmacokinetics of mexiletine in healthy volunteers.

Pringle¹,

Fox²,

Mcneill³

et al. 1986

Brit J Clinical Pharma

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In 12 healthy volunteers who received orally 100, 200, 300, 400 and 600 mg mexiletine at weekly intervals, the maximum plasma concentration of mexiletine and AUC increased linearly with the dose of mexiletine. Between doses there were no significant differences in the values for clearance and volume of distribution of mexiletine but there were for plasma elimination half-life. These results indicate that the kinetics of mexiletine are linear.

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Section: Discussionmentioning

confidence: 89%

Dose independent pharmacokinetics of mexiletine in healthy volunteers.

Pringle¹,

Fox²,

Mcneill³

et al. 1986

Brit J Clinical Pharma

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“…mean) of the dose was excreted as desethylaprindine, whereas after treatment with 3-glucuronidase, 6.6 ± 0.6% and 37.0 ± 10.7% of the dose was recovered as HA1 and HA2, respectively (Ito et al, 1986). It has been proposed that the nonlinear pharmacokinetics of AP observed after multiple dosage (Kobari et al, 1984;Yokota et al, 1987) is caused by saturation of its metabolism. The low capacity of CYP2D6 for the formation of HA1 and HA2, representing the major metabolic pathways, is a reasonable explanation for this finding.…”

Section: Discussionmentioning

confidence: 99%

The metabolism of aprindine in relation to the sparteine/debrisoquine polymorphism.

Ebner

Eichelbaum

1993

Brit J Clinical Pharma

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1 Incubation of the class I antiarrhythmic drug aprindine (AP) with human liver microsomes resulted in the formation of two hydroxylated metabolites (HA1 and HA2) and desethylaprindine which were identified by GC-mass spectrometry. In liver microsomes isolated from a poor metaboliser (PM) of sparteine no hydroxylated metabolites of AP were detected whereas AP N-dealkylation was unimpaired. Thus hydroxylation of AP is mediated by cytochrome P450 2D6 (CYP2D6). 2 AP was found to be a competitive inhibitor of CYP2D6 as indicated by its ability to impair the formation of (2S)-hydroxysparteine, 5,6-didehydrosparteine and 5-hydroxypropafenone by human liver microsomes. 3 These in vitro findings are consistent with a major role of CYP2D6 in the clearance of AP in vivo, with its ability to impair the metabolism of other CYP2D6 substrates in vivo, and an ability to cause phenocopying (conversion of extensive metaboliser phenotypes for sparteine/debrisoquine to apparent 'poor metabolisers).

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“…7) The variation may be related to racial difference in sensitivity to aprindine. More specifically, the pharmacokinetics of aprindine is nonlinear, 7,8) and it is metabolized exclusively by the liver primarily catalyzed by CYP2D6.…”

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confidence: 99%