Valproate glucuronide

Booth CL, Pollack GM, Brouwer KL. Hepatobiliary disposition of valproic acid and valproate glucuronide use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions. Hepatology 1996 23(4) 771-780. 

In rats, lithium pretreatment reduced the plasma half-life of valproate by 25% and increased urinary excretion of valproate glucuronide (609). 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Lamotrigine is metabolized by glucuronidation, possibly by the UGT 1A4 system. As such, it is vulnerable to other UGT inducers—oral contraceptives, phenytoin, carbamazepine, phenobarbital and primidone, and to a UGT inhibitor, valproate (Hachad et ah, 2002). 

Valproate Lorazepam -fr 20% increase in lorazepam AUC, 31% decrease in formation CL of lorazepam glucuronide 40% decrease in lorazepam CL 148,149... 

At a concentration of 100 gg/ml, valproic acid inhibits the glucuronidation of zidovudine in human liver microsomes by 50% (143). This observation explains the previously reported effect of valproate to increase plasma zidovudine concentrations in HIV-infected patients. 

In an attempt to improve the bioavailability of oral 4-OHA, an analogue has been developed [188] in which the 4-hydroxy group is replaced by a fluorine atom (4-fluoroandrostenedione). This compound has similar potency against aromatase, but is less extensively metabolized than 4-OHA. In isolated rat hepatocytes, glucuronidation of this compound is reduced by about 15% compared with 4-OHA [189]. An alternative approach to improving the bioavailability of 4-OHA involves concomitant administration of valproate [189]. In rats, this produces a dose-related reduction in glucuronidation in vivo, but it has not yet been used in clinical trials. 

Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites, contributing to the potential of valproate to cause hepatotoxicity, although this clinical outcome is rare. Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible. 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Not fully understood, but in vitro studies indicate that remaeemide inhibits the cytochrome P450 isoenzyme CYP3A4, which in practice would be expected to result in a reduction in the metabolism of the carbamazepine resulting in an increase in its serum levels. Remaeemide appears to inhibit C YP2C9 to a lesser extent, which is reflected in a smaller interaction with phenytoin. Valproate is metabolised by glucuronidation and is therefore unaffected. ... 

Diflunisal 250 mg twice daily for 7 days given with sodium valproate 200 mg twice daily caused a 20% increase in the unbound fraction of valproate in 7 healthy subjects. There was a 35% increase in the AUC of one of the oxidation metabolites of valproate, and a small decrease in the AUC of some of the diflunisal glucuronide metabolites. This was shown to be due to changes in renal clearance of these metabolites. Whether any of these modest changes have any clinical relevance remains to be seen, but it appears unlikely. 

It seems that valproate reduces the glucuronidation of lorazepam, and therefore benzodiazepines that are mainly metabolised by glucuronide conjugation, such as oxazepam and temazepam are also likely to be affected. It is also thought that valproate may displace midazolam from its... 

The evidence indicates that the metabolism (glucuronidation) of zidovudine is inhibited by valproate so that its bioavailability is increased. It was suggested that this caused zidovudine haematological toxicity in the case reported. The glucuronidation of abacavir is predicted to be increased by drugs that can induce UDP-glucuronyltransferase, such as phenobarbital and phenytoin. ... 

Information seems to be limited to the papers cited, but an interaction between zidovudine and valproate would appear to be established. It would therefore seem prudent to monitor for any evidence of increased zidovudine effects and possible toxicity if valproate is added. The other NRTIs do not undergo significant glucuronidation (see Antivirals , (p.772)), and would therefore not be expected to interact with valproate. For a discussion of drug-disease considerations when using valproate in HIV infection, see under Importance and management in protease inhibitors ,... 

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