Serum Bilirubin Levels with Antiepileptic Drugs

Gough, H; Goggin, T.; Crowley, Michael J.; Callaghan, N.

doi:10.1111/j.1528-1157.1989.tb05478.x

Cited by 15 publications

(5 citation statements)

References 15 publications

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“…It has been well documented that drugs known to activate constitutive androstane receptor (CAR) (eg, phenytoin and phenobarbital) and/or Pregnane X receptor (PXR) (eg, rifampicin and carbamazepine) upregulate the expression of proteins involved in bilirubin disposition, including UGT1A1 and MRP2, 26,27 and thus reduce serum bilirubin concentrations. 28,29 In fact, phenobarbital and rifampicin have been used in the past to treat hyperbilirubinemia. 29,30 Similarly, efavirenz is known to activate CAR 11,31 and possibly PXR, 32 and it is reasonable to suggest that efavirenz, like these PXR/CAR activators, interacts at ≥1 of these sites to enhance the elimination of bilirubin.…”

Section: Discussionmentioning

confidence: 99%

Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

Metzger

Quigg

Epstein

et al. 2014

Current Therapeutic Research

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BackgroundEfavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs.ObjectivesTo explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers.MethodsMen and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported.ResultsData from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin.ConclusionsEfavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.

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Section: Discussionmentioning

confidence: 99%

Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

Metzger

Quigg

Epstein

et al. 2014

Current Therapeutic Research

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“…A gradual increase in UGT-activity, expressed as bilirubin conjugation, as a function of valproate levels has been demonstrated in vivo in mice. 52 The reduction in total bilirubin levels in patients treated with valproic acid as found by Gough et al, 53 may therefore be explained by higher bilirubin conjugation following an inducing effect of valproic acid on hepatic UGT1A. 52 Additionally, an induced UGT1A1-status may explain why in this particular patient bilirubin levels remained normal, whereas liver-enzymes (that is, gGT and transaminases) increased dramatically after administration of irinotecan.…”

Section: Discussionmentioning

confidence: 87%

Irinotecan chemotherapy during valproic acid treatment: Pharmacokinetic interaction and hepatotoxicity

Jong

Bol²,

Mathijssen³

et al. 2007

Cancer Biology & Therapy

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Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drugs.

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“…The finding that UDP-GT levels were lower in the group with hepatic necrosis (compared to those with normal histology) could support the first hypothesis. Clinical studies have demonstrated consistent results in that serum bilirubin levels were significantly reduced in patients receiving phenobarbital, carbamazepine and phenytoin [38]. The mechanism for the reduction of bilirubin level by these drugs has been suggested to be an induction of hepatic microsomal enzyme, glucuronyl transferase [39] or the increased excretion of bilirubin from hepatic cells into bile [40].…”

Section: Discussionmentioning

confidence: 93%

“…The mechanism for the reduction of bilirubin level by these drugs has been suggested to be an induction of hepatic microsomal enzyme, glucuronyl transferase [39] or the increased excretion of bilirubin from hepatic cells into bile [40]. The marginally significant reduction in bilirubin levels in patients treated with VPA which was found by Gough et al [38] has been speculated to be the result of increased excretion of bilirubin from the hepatic cell into the bile. According of patients with VPA-associated hepatotoxicity [21,22,26,27].…”

Section: Discussionmentioning

confidence: 96%

In vivo effect of sodium valproate on mouse liver

Roma-Giannikou

Syriopoulou

Kairis

et al. 1999

Cellular and Molecular Life Sciences (CMLS)

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The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.

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Serum Bilirubin Levels with Antiepileptic Drugs

Cited by 15 publications

References 15 publications

Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

Irinotecan chemotherapy during valproic acid treatment: Pharmacokinetic interaction and hepatotoxicity

In vivo effect of sodium valproate on mouse liver

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