当前位置： SCI文献检索 > BRITISH JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation.

The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation.

Abstract：

:1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O-demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4-hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = -0.83; P = 0.006 and rs = -0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine-type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Broly F,Vandamme N,Libersa C,Lhermitte M

doi

10.1111/j.1365-2125.1991.tb03931.x

subject

Has Abstract

pub_date

1991-10-01 00:00:00

pages

459-66

issue

4

eissn

0306-5251

issn

1365-2125

journal_volume

32

pub_type

杂志文章

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