Drug Interactions with Isoniazid Metabolism in Rats

Thomas, Barb R.; Solomonraj, G.

doi:10.1002/jps.2600660930

Cited by 29 publications

(4 citation statements)

References 13 publications

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“…Isoniazid is acetylated via N-acetyltransferase and these results are consistent with more recent findings on the effects of ethanol upon drug acetylation (Olsen and Morland, 1978). Thomas and Solomonraj (1977) studied the effect of ethanol on the disposition of radiolabelled isoniazid in rats. The fraction of dose eliminated as Nacetylisoniazid was increased and that as isonicotinic acid was decreased.…”

Section: Isoniazid (Inh)supporting

confidence: 88%

Effects of Ethanol on Drug and Metabolite Pharmacokinetics

Lane

Guthrie

Linnoila

1985

Clinical Pharmacokinetics

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Pharmacokinetic interactions of ethanol with other drugs, including its effects upon drug metabolite disposition, are reviewed in terms of clearance concepts. This approach is particularly useful in understanding the mechanisms of ethanol-drug interactions, i.e. in separating the effects of ethanol upon drug clearance, volume of distribution and plasma protein binding. The application of clearance concepts provides the basis for understanding the qualitative differences in ethanol interactions with low and high hepatic extraction ratio drugs. The effects of short and long term ethanol consumption upon different types of drug metabolism (oxidative, acetylation and glucuronidation) have been considered. Long term ethanol consumption may increase the clearance of a drug by induction of oxidative metabolism whereas short term consumption may decrease the clearance of such a drug. Clearance by N-acetylation appears to be increased in the presence of ethanol, and clearance by conjugation to glucuronic acid is decreased for some drugs by single-dose consumption of ethanol.

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Section: Isoniazid (Inh)supporting

confidence: 88%

Effects of Ethanol on Drug and Metabolite Pharmacokinetics

Lane

Guthrie

Linnoila

1985

Clinical Pharmacokinetics

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“…For convenience, rats have been extensively used to investigate the hepatotoxicity of isoniazid treatment together with rifampicin for screening antihepatotoxic drugs ( Attri et al , 2000 ; Tasduq et al , 2005 ; Santhosh et al , 2006 ). In contrast to the synergistic hepatotoxicity seen in humans after co‐administration of isoniazid and rifampicin ( Steele et al , 1991 ; Yew, 2002 ), no such enhancement of isoniazid‐induced hepatotoxicity by rifampicin was observed in rats ( Thomas and Solomonraj, 1977 ; Yue et al , 2004 ). Thus, there is a clear species difference in the exacerbation of isoniazid hepatotoxicity by co‐treatment with rifampicin.…”

Section: Introductionmentioning

confidence: 99%

Rifampicin exacerbates isoniazid‐induced toxicity in human but not in rat hepatocytes in tissue‐like cultures

Shen

Meng

Zhang

et al. 2008

British J Pharmacology

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Background and purpose: Rifampicin has been extensively reported to exacerbate the hepatotoxicity of isoniazid in patients with tuberculosis. However, this was controversially claimed by previous reports using rat models. This study evaluated the effect of rifampicin on isoniazid-induced hepatocyte toxicity by using human and rat hepatocytes in tissue-like culture. Experimental approach: Hepatocytes in tissue-like gel entrapment were used to examine isoniazid toxicity, as shown by cell viability, intracellular glutathione content and albumin secretion. For demonstration of the differential effects of rifampicin on human and rat hepatocytes, induction by rifampicin of cytochrome P450 (CYP) 2E1, a major enzyme associated with isoniazid hepatotoxicity, was detected by 4-nitrocatechol formation and RT-PCR analysis. Key results: Rifampicin (12 mM) enhanced isoniazid-induced toxicity in human hepatocytes but not in rat hepatocytes. Enhanced CYP 2E1 enzymic activity and mRNA expression were similarly detected in human hepatocytes but not in rat hepatocytes. Both rat and human hepatocytes in gel entrapment were more sensitive to isoniazid treatment compared with the corresponding hepatocytes in a monolayer culture. Conclusions and implications:The difference in induction of CYP 2E1 by rifampicin between rat and human hepatocytes accounted for the difference in exacerbation of isoniazid hepatocyte toxicity by rifampicin, with more significant toxicity in gel entrapment than in monolayer cultures. Thus, human hepatocytes in tissue-like cultures (gel entrapment) could be an effective model for hepatotoxicity research in vitro, closer to the in vivo situation.

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“…Other studies also have given support to our findings that acute ethanol administration may increase drug acetylation. Thomas & Solomonraj (1977) found that ethanol treatment increased the excretion of N-acetylisoniazid in rats. Estler (1979) found increased acetylation of isoniazid in mice, and Lester (1964) reported that the half-life of isoniazid was decreased in the presence of ethanol in two test subjects.…”

Section: Discussionmentioning

confidence: 96%

Ethanol‐induced increase in procainamide acetylation in man.

Olsen¹,

Mørland²

1982

Brit J Clinical Pharma

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1 The effect of ethanol on procainamide pharmacokinetics was studied in humans by two different experimental designs. In one, ethanol was given 1.5 h after taking the drug followed by hourly drinks, while in the other ethanol was given 2 h before and subsequently after taking the drug. 2 In both studies, ethanol caused a significant reduction of T1/2 and a significant increase in total clearance of procainamide, while the apparent volume of distribution of procainamide, as well as the renal clearance of both procainamide and N‐acetylprocainamide were unaffected by ethanol treatment. 3 Ethanol treatment increased the percentage of N‐acetylprocainamide measured in blood and urine and the ratio of AUCNAPA/AUCPA significantly. 4 The T1/2 and total clearance of procainamide was significantly different in slow and rapid acetylators.

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Drug Interactions with Isoniazid Metabolism in Rats

Cited by 29 publications

References 13 publications

Effects of Ethanol on Drug and Metabolite Pharmacokinetics

Effects of Ethanol on Drug and Metabolite Pharmacokinetics

Rifampicin exacerbates isoniazid‐induced toxicity in human but not in rat hepatocytes in tissue‐like cultures

Ethanol‐induced increase in procainamide acetylation in man.

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