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

The kinetics at a single oral dose (400 mg) of quinidine were studied in four extensive metabolizers (EM) and four poor metabolizers (PM) of sparteine. The clearance of quinidine by 3-hydroxylation was significantly lower in PM than in EM, but the difference was small (25-30%). This finding suggests that 3-hydroxylation, in part, is catalyzed by the same isoenzyme of cytochrome P450, P450dbl which oxidizes sparteine. Otherwise, no significant phenotypic differences in total or metabolic clearance were found and it is concluded that the metabolism of quinidine is largely carried out by P450 isoenzymes different from P450dbl. A biexponential decline in the log plasma quinidine concentration vs time curves was observed in all subjects, and the mean elimination half-life was 11-12 h. This is about twice as long as generally reported in the literature.

Section: Introductionsupporting

confidence: 51%

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

Brøsen¹,

Davidsen²,

Gram³

1990

“…Accordingly, in vivo studies have shown that EM can change phenotype to PM when treated with therapeutic or even subtherapeutic doses of quinidine (Brinn et al, 1986;Br0sen & Gram, 1989b;Br0sen et al, 1987;Inaba et al, 1986;Leemann et al, 1986;Speirs et al, 1986;Steiner et al, 1988). Even at doses as low as 5 mg, quinidine impairs debrisoquine metabolism in vivo (Boobis et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

A dose‐effect study of the in vivo inhibitory effect of quinidine on sparteine oxidation in man.

Brøsen

Gram

1990

1. Twelve healthy extensive metabolisers of sparteine were sparteine tested daily for 6 days (19.00 h to 07.00 h). A small but statistically significant rise in sparteine metabolic ratio (MR) was observed. 2. Following 100 mg quinidine sulphate given to four of the subjects at 16.00 h, sparteine tests were carried out 19.00 h to 07.00 h on the same day and then daily for 6 days. Quinidine caused an immediate twenty‐fold increase in sparteine‐MR which then gradually returned to normal over the following 4‐6 days. Quinidine concentrations in plasma were measurable only up to 20 h after the quinidine test dose. 3. At weekly intervals, all 12 subjects received single doses of quinidine sulphate of 5, 10, 20, 40 and 80 mg at 16.00 h, each time followed by a sparteine test 19.00 h to 07.00 h on the same day. A clear dose‐effect relationship was found with a significant rise in the sparteine‐MR even after 5 mg quinidine. After 80 mg quinidine, 8 of 12 subjects became phenotypically poor metabolisers (MR greater than 20).

“…An in vitro screening test has been developed in which the ability of a given compound to competitively inhibit the oxidation of sparteine or debrisoquine in microsomal preparations from human liver is examined (Otton etal., 1983;Boobis etal., 1983;Inaba et al, 1985). Quinidine is a very potent in vitro (Otton et al, 1984) and in vivo inhibitor of sparteine and debrisoquine oxidation (Brinn et al, 1986;Speirs et al, 1986;Br0sen et al, 1987), but in vitro, panel, and clinical studies indicate that its elimination via the sparteine oxygenase is limtied (Mikus etal., 1986;Brinn et al, 1986;Gram & Br0sen, 1988). Several neuroleptics, among them haloperidol, are also potent in vitro inhibitors of the sparteine oxygenase (Inaba et al, 1985), and are clinically potent inhibitors of the metabolism of tricyclic antidepressants (Gram & Over0, 1972;Gram 1975;Gram et al, 1984; press).…”

Section: Introductionmentioning

confidence: 99%

Substantial rise in sparteine metabolic ratio during haloperidol treatment.

Gram

Debruyne

Caillard

et al. 1989

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-'. In patients classified as extensive metabolisers (sparteine MR < 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-' was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).