Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes.

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Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A

Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes.

Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2.

PubMed ID

15933229 [ View in PubMed

]

Abstract

Here we present a preclinical model to assess drug-drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.2 mM). In contrast, pretreatment with PB for 48 h prior to APAP treatment did not increase APAP toxicity unless both drugs were present simultaneously. Cells treated with APAP in combination with PB or PH experienced decreases in protein synthesis as early as 1 h, ultrastructural changes by 24 h, and release of liver enzymes by 48 h. Toxicity correlated with inhibition of APAP glucuronidation. PB or PH also inhibited APAP glucuronidation in rat and human liver microsomes and expressed human UGT1A6, 1A9, and 2B15. As with intact hepatocytes, PB and PH were neither hydroxylated nor glucuronidated, suggesting the direct inhibition of UGTs. Our findings suggest that, in multiple drug therapy, an inhibitory complex between UGT and one of the drugs can lead to decreased glucuronidation and increased systemic exposure and toxicity of a coadministered drug.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Fosphenytoin	UDP-glucuronosyltransferase 1-6	Protein	Humans	No	Inhibitor	Details
Fosphenytoin	UDP-glucuronosyltransferase 1-9	Protein	Humans	No	Inhibitor	Details
Phenytoin	UDP-glucuronosyltransferase 1-6	Protein	Humans	No	Substrate Inhibitor	Details
Phenytoin	UDP-glucuronosyltransferase 1-9	Protein	Humans	No	Substrate Inhibitor	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Acetaminophen Methohexital	The metabolism of Acetaminophen can be increased when combined with Methohexital.
Acetaminophen Methylphenobarbital	The metabolism of Acetaminophen can be increased when combined with Methylphenobarbital.
Acetaminophen Thiamylal	The metabolism of Acetaminophen can be increased when combined with Thiamylal.
Acetaminophen Amobarbital	The metabolism of Acetaminophen can be increased when combined with Amobarbital.
Acetaminophen Hexobarbital	The metabolism of Acetaminophen can be increased when combined with Hexobarbital.