The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases

Ethell, Brian T.; Anderson, Gail D.; Burchell, Brian

doi:10.1016/s0006-2952(03)00076-5

Cited by 130 publications

(83 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Trans-3?-hydroxycotinine O-glucuronidation in human liver microsomes was signiˆcantly correlated with valproic acid glucuronidation, which is catalyzed by UGT2B7, UGT1A6, and UGT1A9. 54) Trans-3?-hydroxycotinine O-glucuronidation in human liver microsomes was inhibited by imipramine (UGT1A4), propofol (UGT1A9), and androstanediol (UGT2B15). However, it was conˆrmed that these three compounds inhibited trans-3?-hydroxycotinine O-glucuronosyltransferase activity catalyzed by recombinant UGT2B7 with more potent inhibitory eŠects than those in human liver microsomes.…”

Section: Trans-3?-hydroxycotinine O-glucuronidationmentioning

confidence: 99%

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Nakajima

Yokoi

2005

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Summary: Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3?-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3?-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90z of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual diŠerences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic diŠerences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3?-hydroxycotinine in humans would be one of the causal factors for the interindividual diŠerences in nicotine metabolism. This review mainly summarizes recent results from our studies.

show abstract

Section: Trans-3?-hydroxycotinine O-glucuronidationmentioning

confidence: 99%

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Nakajima

Yokoi

2005

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

show abstract

“…In the present study, we used mefenamic acid (a substrate of UGT1A9 and an inhibitor of UGT2B7), valproic acid (a substrate of UGT1A6, 1A9, and 2B7), AZT (a substrate of UGT2B7), and baicalein (a substrate of the UGT1A subfamily). 17,[27][28][29][30] Figure 2 shows the percentage of metabolized R-and S-carvedilol following 24-h incubation with b-NF-treated Caco-2 cells in the absence and presence of 500 mM substrates of UGTs. Mefenamic acid and valproic acid had no effect on the metabolism of R-and S-carvedilol.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Ishida

Honda

Shimizu

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and is absorbed rapidly from the gastrointestinal tract after oral administration. Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of R-enantiomer with very low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity. 5,6) Both enantiomers are eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 7) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.8) Oldham and Clarke reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. 9) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. 10) However, it is still unclear which enzyme is responsible for the stereoselective presystemic clearance of carvedilol. Furthermore, although CYP3A4 and several UGTs are expressed in intestinal epithelial cells, it is also unknown whether the intestine as well as the liver is involved in the first-pass metabolism of carvedilol.The approach for investigating intestinal drug absorption and metabolism is to use human intestinal cell lines, such as the frequently used line Caco-2. This line spontaneously differentiates, after which it shows enterocyte-like morphology and forms polarized monolayers via tight junctions. It also expresses various transporters and efflux pumps such as P-glycoprotein.11,12) Therefore, it has been utilized to examine the mechanism responsible for the intestinal absorption of various compounds. 12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF).14,15) Therefore, glucuronidation of drugs in the intestine has been studied using Caco-2 cells. [16][17][18] In contrast, the Caco-2 cell line had not been employed to examine the intestinal metabolism of CYP3A4 substrates due to its lack of CYP3A4 expression. Recently, however, it has been reported that CYP3A4 in Caco-2 cells is induced by 1a,25-dihydroxyvitamin D 3 (VD 3 ). 11,19) The finding suggests that this cell line may also be utilized to investigate intestinal drug metabolism by CYP3A4. In the present study, we investigated whether carvedilol is metabolized stereoselectively in Caco-2 cells, and also evaluated the changes in the metabolic rate of carvedilol in b-NF-and VD 3 -treated Caco-2 cells. MATERIALS AND METHODS MaterialsCarvedilol was kindly supplied by Daiichi Pharmaceutical (Tokyo, Japan). b-NF was obtained from Nacalai Tesque (Kyoto, Japan). VD 3 and 3Ј-azido-3Ј-deoxythimidine (AZT...

show abstract

“…2). It is reported that the UGT isoforms catalyzing VPA glucuronidation in humans are UGT1A6, UGT1A9 and UGT2B7 (corresponding in rat UGT2B1), but the activity of UGT1A9 in liver is low [18]. Therefore, UGT2B1 is the main determinant of the activity level of UGT s for VPA glucuronidation in rats, and so it appears that VPA glucuronidation is little influenced by chronic hepatic failure, as judged from the unchanged expression of UGT2B1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…1). UGT1A8 is highly expressed in intestine, where it acts to block enterohepatic recirculation of drugs that have undergone glucuronidation and subsequent hydrolysis of the glucuronide by β-glucuronidase [18]. Therefore, regeneration of VPA from VPA-G in the intestinal tract is likely to be minor in rats with chronic hepatic failure, because UGT1A8 is induced.…”

Section: Discussionmentioning

confidence: 99%

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

Khemawoot

Maruyama

Tsukada

et al. 2007

Biopharm & Drug Disp

View full text Add to dashboard Cite

Abstract:We examined the influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was significantly reduced, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentrationtime curve is significantly decreased in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G.

show abstract

The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases

Cited by 130 publications

References 22 publications

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

Contact Info

Product

Resources

About