The metabolism and excretion of enzyme-inducing doses of phenobarbital by rats with bile fistulas

Levin, Scott; Vars, Harry M.; Schleyer, Heinz; Cooper, David Y.

doi:10.3109/00498258609043524

Cited by 10 publications

(8 citation statements)

References 8 publications

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“…An exhaustive mass spectral analysis of the microsomal extracts showed trace quantities of a hydroxylated metabolite. This finding is consistent with the observations made by previous investigators who found lack of in vitro metabolism of PB in microsomal systems and in cultured rat hepatocytes (Levin et al, 1986;Verite et al, 1996). However it has been shown in vivo that PB is metabolized in rats and humans with the formation of a hydroxylated metabolite that is subsequently conjugated with glucuronic acid (Levin et al, 1986;Whyte et al, 1977).…”

Section: Effect Of Phenobarbital and Phenytoin On Apap Glucuronidation By Expressed Forms Of Human Ugts And Human Liver Microsomessupporting

confidence: 92%

Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes

Kostrubsky¹,

Sinclair²,

Strom³

et al. 2005

Toxicological Sciences

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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.

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Section: Effect Of Phenobarbital and Phenytoin On Apap Glucuronidation By Expressed Forms Of Human Ugts And Human Liver Microsomessupporting

confidence: 92%

Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes

Kostrubsky¹,

Sinclair²,

Strom³

et al. 2005

Toxicological Sciences

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“…Twenty-five percent of PB is cleared by renal excretion in unchanged form [87]. After administration, PB was detected in hepatic tissue and the portal vein, vena cava, and aorta [88], suggesting that the liver is the main organ for the metabolism of PB. The metabolites of PB include free PB and two inactive metabolites.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

Fan

Lee

Chang

et al. 2016

IJMS

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Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.

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“…PB, p-OHPB and p-OHPBG are the major species found in bile after a dose of PB (Levin et al, 1986). Among them, only p-OHPBG markedly inhibited Mrp2-mediated CDF uptake.…”

Section: Mechanisms Of Impaired Biliary Excretion Of Ag By Pb (52)mentioning

confidence: 99%

“…PB is metabolized in the liver by cytochrome P450 enzymes to p-hydroxyphenobarbital ( p-OHPB), which is metabolized further primarily to p-hydroxyphenobarbital glucuronide ( p-OHPBG). In rats with bile fistula, approximately 20 to 30% of the PB dose recovered in bile was the parent compound, and 50 to 60% was free or conjugated p-OHPB (mainly p-OHPBG) (Levin et al, 1986). The transport mechanisms for biliary excretion of PB, p-OHPB, and p-OHPBG have not been clarified.…”

mentioning

confidence: 99%

Mechanisms of Impaired Biliary Excretion of Acetaminophen Glucuronide after Acute Phenobarbital Treatment or Phenobarbital Pretreatment

Xiong

Suzuki

Sugiyama³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Previous studies have demonstrated that phenobarbital (PB) significantly impairs the biliary excretion of acetaminophen glucuronide (AG) in rats. Studies also suggested that Mrp2 mediates AG biliary excretion, and Mrp3 is involved in AG basolateral export. It was hypothesized that inhibition of Mrp2-mediated AG transport by PB or PB metabolites, and PB induction of Mrp3, may contribute to the impaired biliary excretion of AG by PB. In the present study, the hepatobiliary transport of AG in single-pass isolated perfused Wistar and TR ؊ rat livers was investigated. Acetaminophen glucuronide (AG 1 ), a monovalent organic anion formed in hepatocytes following acetaminophen (APAP) administration, undergoes both biliary excretion and basolateral export from hepatocytes. Approximately 50% of AG formed in hepatocytes is excreted in bile; the remainder traverses the basolateral membrane into blood and undergoes renal elimination. AG excretion in bile accounts for ϳ7% of the administered APAP dose (100 mg/kg) in rats in vivo (Brouwer and Jones, 1990) and ϳ10% in the isolated perfused rat liver at equivalent APAP concentrations (Studenberg and Brouwer, 1992;Turner and Brouwer, 1997). Pretreatment with phenobarbital (PB), a common enzyme-inducing agent, significantly increased AG formation but impaired AG biliary excretion 3-to 6-fold in the rat in vivo (Brouwer and Jones, 1990) and in the isolated perfused rat liver (Studenberg and Brouwer, 1992). Acute PB treatment also markedly (ϳ3-fold) decreased the biliary excretion of AG along with a moderate reduction (ϳ1.5-fold) in AG formation (Studenberg and Brouwer, 1992).Several distinct mechanisms may be involved in decreased biliary excretion of AG after PB treatment. Previous studies suggested that the decrease in APAP glucuronidation may contribute in part to the impaired biliary excretion of AG after acute PB treatment. Intracellular sequestration of AG does not play a role in the reduction in AG biliary excretion after either PB pretreatment or acute PB treatment Brouwer, 1992, 1993). PB is a well-known enzyme inducer that also induces hepatocyte basolateral transporters, multidrug resistance-associated protein 3 (Mrp3; Abcc3), and organic anion transporting polypeptide 2 (Oatp2; Slc21a5), in Sprague-Dawley rats (Ogawa et al., 2000; Rausch-Derra et al., 2001). PB pretreatment may

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The metabolism and excretion of enzyme-inducing doses of phenobarbital by rats with bile fistulas

Cited by 10 publications

References 8 publications

Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes

Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

Mechanisms of Impaired Biliary Excretion of Acetaminophen Glucuronide after Acute Phenobarbital Treatment or Phenobarbital Pretreatment

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