Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection

125

1 A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3-and 6-glucuronides (M3G and M6G) + normorphine)), N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM))) and glucuronidation (codeine/codeine-6-glucuronide (C6G)) were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2 There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (r, = 0.77, P < 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3 The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4 The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5 No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6 The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.

Section: Methodsmentioning

confidence: 99%

Codeine O‐demethylation co‐segregates with polymorphic debrisoquine hydroxylation.

Svensson

Alm

et al. 1989

125

“…Urinary metoprolol / a -hydroxymetoprolol (M/HM) (Lennard, 1985) and debrisoquine/4-hydroxydebrisoquine (D/HD) ratios (Lennard et al, 1977) were measured as described pre-viously. The analysis of metoprolol enantiomers was based on the h.p.l.c.…”

Section: Methodsmentioning

confidence: 99%

Stereoselective metabolism of metoprolol in Caucasians and Nigerians‐ relationship to debrisoquine oxidation phenotype.

Lennard

Tucker

Woods

et al. 1989

The relationship between debrisoquine oxidation phenotype and the stereoselective metabolism of metoprolol was investigated in populations of British Caucasians (n = 139) and Nigerian subjects (n = 117). The 0-8 h urinary S/R-metoprolol (S/R-M) ratio was related to the ability to metabolise metoprolol and debrisoquine in both ethnic groups. The median S/R-M ratio was significantly higher in Caucasians (1.27) than in Nigerians (1.10). In the Caucasian population poor metabolisers of debrisoquine had significantly lower S/R-M ratios (median = 0.84) than extensive metabolisers (median = 1.28). Bimodality in the frequency distribution of the S/R-M ratio was not apparent in either ethnic group.

“…Urine concentrations of debrisoquine and its 4-hydroxy metabolite were assayed as described by Lennard [7]. Maprotiline concentrations in plasma were measured using a modified h.p.l.c.…”

Section: Analytical Proceduresmentioning

confidence: 99%

Maprotiline metabolism appears to co‐segregate with the genetically‐ determined CYP2D6 polymorphic hydroxylation of debrisoquine.

Firkusny¹,

Ch²

1994

The plasma concentrations of the tetracyclic antidepressant maprotiline and its effect on histamine‐induced bronchoconstriction were measured after single (50 mg) and multiple (50 mg twice daily) oral doses in healthy subjects. Histamine‐induced bronchoconstriction was abolished after a single dose of maprotiline and this effect persisted throughout multiple dose treatment. The mean Cmax of maprotiline in six poor metabolisers (PM) of debrisoquine was 2.7‐fold greater than that in six extensive metabolisers (EM) and the mean AUC(0,48 h) was 3.5 times higher. The duration of the pulmonary effect of maprotiline after cessation of multiple dose treatment in EM was less than 3 weeks compared with at least 4 weeks in PM.