The genetic controlof bufuralol metabolisminman

Eight samples of human liver have been characterised for microsomal protein content, cytochrome P450 content, tolbutamide 4-hydroxylase and ethinyloestradiol 2-hydroxylase activities. Cytochrome P-450 content correlated significantly with ethinyloestradiol 2-hydroxylase activity but not with tolbutamide 4-hydroxylase activity. There was no significant correlation between ethinyloestradiol 2-hydroxylase and tolbutamide 4-hydroxylase activities. The maximum tolbutamide 4-hydroxylase activity was 0.45 nmol min-' mg-1 microsomal protein, with a Km value of 74 FLM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non-competitive or mixed non-competitive inhibitors of tolbutamide 4-hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P-450 which appears to be distinct from those isozymes metabolising many other drugs.

Section: Resultsmentioning

confidence: 99%

Tolbutamide 4‐hydroxylase activity of human liver microsomes: effect of inhibitors.

Purba

Back

Orme

1987

“…bufuralol (Dayer et al, 1982) are impaired in the PM phenotype in vivo and both activities are reduced in biopsy samples from phenotyped PM subjects Minder et al, 1983 …”

Section: Resultsmentioning

confidence: 99%

Attempts to phenotype human liver samples in vitro for debrisoquine 4‐ hydroxylase activity.

Boobis¹,

Hampden²,

Murray³

et al. 1985

Twenty‐eight samples of human liver have been characterised for cytochrome P‐450 content, aldrin epoxidase, debrisoquine 4‐hydroxylase and bufuralol 1'‐hydroxylase activities. Evidence is presented here and elsewhere that bufuralol 1'‐hydroxylase and debrisoquine 4‐hydroxylase are activities catalysed by the same form of cytochrome P‐450 in man, and that this form is different from that catalysing the epoxidation of aldrin. Attempts to phenotype liver samples in vitro, in the absence of any metabolic data in vivo for debrisoquine 4‐hydroxylation status, met with limited success. A combination of enzyme assays will most probably be required in any such phenotyping of human liver samples.

“…Thus studies in sparteine/debrisoquine phenotyped subjects have indicated that the overall elimination of metoprolol (Lennar et al, 1982), timolol (Lewis et al, 1985) and bufuralol (Dayer et al, 1982) is associated largely with this isozyme, whereas the oxidation of propranolol is only partially affected (Lennard etal., 1984;Raghuram et al, 1984). Therefore, the present findings suggest that quinidine may also inhibit the oxidative metabolism of these drugs, and a recent study on metoprolol confirms this (Leeman et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Sparteine oxidation is practically abolished in quinidine‐treated patients.

Brinn

Brøsen²,

Gram³

et al. 1986

In eight patients a sparteine-test was carried out immediately before and after 1 week of treatment with quinidine 600-800 mg dayf1. Before treatment one patient was classified as a poor metaboliser (metabolic ratio: : 20), and seven patients as extensive metabolisers. During quinidine treatment, the formation of sparteine metabolites (2-and 5-dehydrosparteine) was practically abolished. Patients initially classified as extensive metabolisers thus exhibited the phenotype of poor metabolisers during quinidine treatment.