Phenobarbital-induced drug metabolism in man

Kellermann, Gottfried; Luyten-Kellermann, Mieke

doi:10.1016/0041-008x(77)90181-8

Cited by 13 publications

(2 citation statements)

References 13 publications

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“…For example, exposure of humans to inducers of animal cytochromes P-450 including such drugs as phenobarbital (6), macrolide antibiotics (7), or diphenylhydantoin (8), or environmental chemicals such as organochlorine pesticides (9) or polychlorinated biphenyls (10), accelerates the disappearance of administered substrates for the cytochromes P-450 from the blood or the appearance of metabolites of such model drugs in the breath (11). Such patients may also exhibit increased urinary excretion of metabolites of endogenous substrates such as 6,8-hydroxy derivatives of cortisol (12)(13)(14)(15).…”

mentioning

confidence: 99%

Identification of an inducible form of cytochrome P-450 in human liver.

Watkins¹,

Wrighton²,

Maurel³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

232

141

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It has not yet been determined whether human liver contains inducible cytochromes P-450 similar to those that catalyze the oxidative metabolism of foreign substances in animals. We carried out immunoblot analyses of liver microsomes isolated from eight patients and found that each contained a cytochrome P-450, termed HLp, that reacted with antibodies directed against P-450p, a rat liver cytochrome that is inducible by the anti-glucocorticoid pregnenolone-16a-carbonitrile, by glucocorticoids, by anti-seizure drugs, and by such macrolide antibiotics as triacetyloleandomycin. In the two patients who received dexamethasone and anti-seizure medications and in the one patient who was given triacetyloleandomycin, the concentrations of immunoreactive HLp and the ability to demethylate erythromycin and/or to convert triacetyloleandomycin to a metabolite that forms a spectral complex with cytochrome P-450 heme (catalytic properties unique to P-450p in rat liver) were significantly higher as compared to the values for patients who received no inducing drugs. We purified HLp to homogeneity and found that it was immunochemically related to P-450p and to its homologue in the rabbit (LM3c), actively demethylated erythromycin in a reconstituted system, exhibited electrophoretic mobility identical to that of P-450p, and shared 57% homology in its NH2-terminal amino acid sequence with that of a pregnenolone16a-carbonitrile-inducible rat cytochrome P-450. We conclude that HLp is a human representative of the multigene family of the glucocorticoid-inducible cytochromes P-450.The cytochromes P-450 are a family of hemoproteins, abundant in the endoplasmic reticulum of the hepatocyte, that catalyze the oxidative metabolism of many drugs, environmental chemicals, and endogenous compounds (1). An important characteristic of some of the forms of cytochrome P-450 is that they are inducible. For example, different forms of liver cytochrome P-450 accumulate in rats treated by a member of one of three "classes" of inducers (as reviewed in ref.2) typified, respectively, by phenobarbital (P-450b, P-450e), 3-methylcholanthrene (P-450c, P-450d), and pregnenolone-16a-carbonitrile (PCN) (P-450p). Since the amounts and types of cytochromes P-450 in the liver may be rate-limiting for metabolism of foreign chemicals, enzyme induction may play an important role in such clinically relevant phenomena as interactions among therapeutic drugs (3), metabolic "idiosyncrasy" in hepatotoxic drug reactions (4), and interindividual differences in susceptibility to toxic effects of environmental chemicals (5).There is abundant, albeit indirect, evidence that human liver also contains cytochromes P-450 that are inducible. For example, exposure of humans to inducers of animal cytochromes P-450 including such drugs as phenobarbital (6), macrolide antibiotics (7), or diphenylhydantoin (8), or environmental chemicals such as organochlorine pesticides (9) or polychlorinated biphenyls (10), accelerates the disappearance of administered substrates for the cytochr...

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mentioning

confidence: 99%

Identification of an inducible form of cytochrome P-450 in human liver.

Watkins¹,

Wrighton²,

Maurel³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

232

141

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“…The dose and duration of phenobarbital treatment should have been adequate to induce hepatic enzymes. 9 It was considerably larger than that usual in the combination tablets with theophylline. Analysis of blood samples at two stages of phenobarbital treatment indicated that subjects so treated were taking the medication in the prescribed manner.…”

Section: Discussionmentioning

confidence: 86%

Effect of phenobarbital on the disposition of intravenous theophylline

Piafsky¹,

Sitar²,

Ogilvie³

1977

Clin Pharma and Therapeutics

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Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

Benedek

Davidson

Pieniaszek

1994

The Journal of Clinical Pharma

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Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

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Phenobarbital-induced drug metabolism in man

Cited by 13 publications

References 13 publications

Identification of an inducible form of cytochrome P-450 in human liver.

Identification of an inducible form of cytochrome P-450 in human liver.

Effect of phenobarbital on the disposition of intravenous theophylline

Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

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