Accumulation of debrisoquine by platelets in vivo: a model of events at the peripheral adrenergic neurone.

Silas, J H; Tucker, GT; Smith, A. J.; Fieller, Nick

doi:10.1111/j.1365-2125.1980.tb01071.x

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…During NTtreatment the uptake of debrisoquine might be inhibited and more of the drug or metabolite excreted in urine. In healthy subjects given a single dose of amitriptyline the accumulation of debrisoquine by platelets was inhibited (Silas et al, 1980 …”

Section: Resultsmentioning

confidence: 95%

Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.

Nordin¹,

Siwers²,

Benitez³

et al. 1985

Brit J Clinical Pharma

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In 20 depressed patients treated with nortriptyline (NT) there was a significant relationship between the plasma concentration of NT and the debrisoquine metabolic ratio (rs = 0.77; P less than 0.01). (The debrisoquine test was performed after stopping NT treatment). This is in agreement with the hypothesis that the hydroxylations of NT and debrisoquine are mediated by similar enzymatic mechanisms. In contrast there was no significant relationship between the debrisoquine metabolic ratio and the plasma concentrations of the active metabolite 10‐hydroxy‐nortriptyline. In 11 of the patients the debrisoquine metabolic ratio was significantly higher during than after NT treatment. This may be due to an inhibition of the debrisoquine hydroxylation by NT.

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Section: Resultsmentioning

confidence: 95%

Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.

Nordin¹,

Siwers²,

Benitez³

et al. 1985

Brit J Clinical Pharma

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“…Assuming that the absorption of debrisoquine is first order, then the hepatic concentration of the drug after a 1 mg dose must be well below saturation. The peak plasma concentration of debrisoquine after an oral dose of 10 mg is approximately 0.09 JIM (Silas et al, 1978(Silas et al, , 1980. The Km for debrisoquine 4-hydroxylase activity of human liver is 125 JIM (Boobis et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Speirs¹,

Murray²,

Boobis³

et al. 1986

Brit J Clinical Pharma

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Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4-hydroxylation of debrisoquine, the O-deethylation of phenacetin and the l'-hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4-hydroxylation in vivo. Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the l'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 /M, being around 100 times more potent in this respect than quinine. Very much higher (1000-fold) levels of quinidine were required to inhibit the O-deethylation of phenacetin, being rather less potent in this than-quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co-administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26-fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.

show abstract

Accumulation of debrisoquine by platelets in vivo: a model of events at the peripheral adrenergic neurone.

Cited by 2 publications

References 19 publications

Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.

Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

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