Drug metabolism in epileptics: in vivo and in vitro correlations.

Ea, Sotaniemi; Pelkonen, R; Ahokas, JT; Pirttiaho, H; Ahlqvist, Johan

doi:10.1111/j.1365-2125.1978.tb01600.x

Cited by 54 publications

(7 citation statements)

References 16 publications

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“…This finding was somewhat surprising in the light of the apparent induction of cytochrome P-450 in the present study and of the fact that we and others have previously demonstrated the induction of several monooxygenases and cytochrome P-450 in human liver biopsy samples by inducing drugs (e.g. Schoene et al, 1972;Sotaniemi et al, 1978b). Furthermore, the enzyme is inducible by phenobarbitone in mouse liver microsomes (Wood & Conney, 1974 flavone, SKF-525A, metyrapone, aniline and testosterone.…”

Section: /[S]contrasting

confidence: 70%

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Pelkonen¹,

Ea²,

Ahokas³

1985

Brit J Clinical Pharma

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Coumarin 7‐hydroxylation and other cytochrome P‐450‐associated enzyme activities were studied in human liver biopsy homogenates and compared with activities in livers of other species. Coumarin 7‐hydroxylation is extraordinarily active in human liver biopsy samples in vitro. Activity is lower in mouse, rabbit or guinea pig liver and essentially absent in rat liver. Cytochrome P‐450 content and other associated enzyme activities were higher in animals. Coumarin 7‐hydroxylation is induced by phenobarbitone in mouse liver, but no significant increase was seen in human or rat liver after exposure to inducers. Correlations amongst coumarin 7‐hydroxylase, aryl hydrocarbon hydroxylase, 7‐ethoxycoumarin O‐deethylase and cytochrome P‐450 are statistically significant (r values from 0.56 to 0.73), but do not permit the conclusion, that the same P‐450 form catalyzes all the reactions studied. The correlations between coumarin hydroxylation and antipyrine half‐life or clearance are statistically significant, but not good enough for predictive purposes. Coumarin 7‐hydroxylase in human liver is inhibited by alpha‐ naphthoflavone, SKF 525A, metyrapone and aniline.

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Section: /[S]contrasting

confidence: 70%

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Pelkonen¹,

Ea²,

Ahokas³

1985

Brit J Clinical Pharma

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“…Phenytoin, carbamazepine, phenobarbitone and primidone, when administered in therapeutic doses to patients with epilepsy, are potent inducers of hepatic drug-metabolising enzymes (Perucca and Richens, 1981;Perucca et al, 1979;Sotaniemi et al, 1978). A number of clinically important drug interactions are considered to be mediated by this effect.…”

Section: Drugs Whose Metabolism May Be Stimulated By Anticonvulsantsmentioning

confidence: 98%

Pharmacokinetic Interactions with Antiepileptic Drugs

Perucca

1982

Clinical Pharmacokinetics

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A large number of pharmacokinetic interactions with antiepileptic drugs have been reported in recent years. Among the interactions affecting the disposition of anticonvulsants, the most important are probably those resulting in inhibition of the metabolism of phenytoin, phenobarbitone and carbamazepine. Drugs which have been shown to inhibit the metabolism of these anticonvulsants and to precipitate clinical signs of intoxication in epileptic patients include sulthiame, valproic acid, chloramphenicol, certain sulphonamides, phenylbutazone, isoniazid and propoxyphene. Interactions affecting the plasma protein binding of antiepileptic drugs are less likely to cause long-lasting alterations in response, but they are important because they change the relationship between serum drug concentrations and clinical effect. Anticonvulsant agents may induce important alterations in the pharmacokinetics of other drugs. Phenytoin and phenobarbitone may decrease the gastrointestinal absorption of frusemide and griseofulvin, respectively. Many of the drugs used in the treatment of the adult epilepsies, including phenytoin, phenobarbitone, primidone and carbamazepine, are potent inducers of the hepatic microsomal enzymes. This results in an increased rate of metabolism and decreased clinical efficacy of a number of drugs, including dicoumarol, steroid oral contraceptives, metyrapone, glucocorticoid agents, doxycycline, quinidine and vitamin D.

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“…Our previous investigations have shown a clear correlation between the capacity of the hepatic drug oxidizing enzyme system in vitro, measured by cytochrome P-450, and drug metabolism in vivo Sotaniemi et al, 1977;Sotaniemi, Pelkonen, Ahokas, Pirttiaho & Ahlqvist, 1977;Pirttiaho, Sotaniemi, Ahokas & Pitkiinen, 1978;Pirttiaho, Sotaniemi, Pelkonen & Pitkiinen, 1978). This was also true in the present study, cytochrome P-450 concentration correlating with propranolol plasma clearance.…”

Section: Discussionmentioning

confidence: 99%

Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.

Pirttiaho¹,

Ea²,

Pelkonen³

et al. 1980

Brit J Clinical Pharma

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1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P450) indices of the activity of the hepatic mixed function oxidase system.3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.

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Drug metabolism in epileptics: in vivo and in vitro correlations.

Cited by 54 publications

References 16 publications

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Pharmacokinetic Interactions with Antiepileptic Drugs

Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.

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