Zur Pharmakokinetik von Meprobamat bei chronischen Hepatopathien und Arzneimittelsucht

Held, H.; Oldershausen, H. F. v.

doi:10.1007/bf01745770

Cited by 29 publications

(2 citation statements)

References 14 publications

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“…are concerned, Held and coworkers (18,19) found meprobamate metabolism reduced in patient with chronic liver disease while the metabolism of pentobarbital was not significently different from normal controls. Tolbutamide metabolism was reported by Ueda (20) to be reduced in liver disease but this finding was not confirmed by other investigators.…”

Section: Discussionsupporting

confidence: 84%

Alteration of Drug Metabolism During Cholestasis in Man*

Carulli

Manenti

Leòn

et al. 1975

Eur J Clin Investigation

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The morphological and functional alterations of the smooth endoplasmic reticulum of the liver cell related to biliary stasis have brought attention to drug biotransformation during cholestasis. The metabolism of meprobamate, pentobarbital and tolbutamide was assessed in subjects with intrahepatic recurrent cholestasis (3), cholestatic hepatitis (6), extrahepatic biliary obstruction (7) and normal controls (16). In the patients with recurrent intrahepatic cholestasis no differences in drug metabolism were noted as compared to the control group. In cholestatic hepatitis the plasma half-lives of meprobamate (828 +/- 422 min.) and pentobarbital (39+-65) were significantly longer than in in controls (444 +/- 37 and 25.4 +/- 1.1 respectively). Tolbutamide plasma half-life appeared unchanged. The most striking variations were observed in the patients with extrahepatic biliary obstruction. In such cases while meprobamate half-life was unchanged, pentobarbital half-life was significantly prolonged (31.2 +/- 2.5) and the in vitro metabolism of the drug, using liver preparations, was decreased to less than 50% of the control value. In contrast the metabolism of tolbutamide was accelerated as evidenced by a significant decrease of plasma half-life (165 +/- 48 min. versus 384 +/- 76 of the controls) and an enhanced urinary excretion of the drug's metabolites. However the metabolism of tolbutamide in vitro did not show any difference between normal and cholestatic liver. Whatever the mechanism of the peculiar behaviour of tolbutamide in extrahepatic biliary obstruction it seems to be related to the increased bile dalt concentration during cholestasis. In fact the low values of plasma half-life increase significantly either relieving the biliary obstruction or producing a bile salt depletion with cholestyramine. Preliminary results in vitro suggest the bile salt could displace tolbutamide from albumin binding thus increasing the amount of free drug available for biotransformation by the liver. In conclusion cholestasis may affect drug metabolism depending on the degree of biliary stasis, liver cell injury and the type of drug tested. The mechanism could be that of an impaired biotransformation in the smooth endoplasmic reticulum or could involve extrahepatic factors.

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Section: Discussionsupporting

confidence: 84%

Alteration of Drug Metabolism During Cholestasis in Man*

Carulli

Manenti

Leòn

et al. 1975

Eur J Clin Investigation

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“…2 , 14, 32 There is also evidence that rates of drug elimination are enhanced after treatment with these drugs in some patients with liver disease 4 , 21 but it is not clear whether microsomal oxidases are induced by drug ingestion in all patients with liver disease. 7,16,37 The activity of hepatic drug oxidases has been related to differences in drug elimination rates between species, 31 between sexes,t3 after drug exposure,8 and after liver injury29 in experimental animals, but Davies et al lo could find no correlation between antipyrine clearance and ethylmorphine demethylase in a small group of normal human subjects. May et al 26 have also reported that there is little relationship between antipyrine half life (AP t1/2) and hepatic cytochrome P-450 concentration except that both are influenced by liver disease and chronic drug ingestion.…”

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confidence: 99%