Effect of valpromide on the pharmacokinetics of carbamazepine‐10, 11‐ epoxide.

Pisani, Francesco; Fazio, A.; Oteri, G.; Spina, Edoardo; Perucca, Emilio

doi:10.1111/j.1365-2125.1988.tb03354.x

Cited by 23 publications

(11 citation statements)

References 12 publications

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“…Felbamate was soluble in the matrix at these concentrations as judged by linearity (10 -1000 M) of UV absorbance when analyzed by HPLC. Valproic acid at 1 mM was used as control for epoxide hydrolase inhibition since this concentration was reported as relevant to the in vivo concentration at which this compound causes inhibition of carbamazepine-diol formation in vivo (Pisani et al, 1988;Ogiso et al, 1990). Final organic solvent concentration was 0.25% DMSO.…”

Section: Methodsmentioning

confidence: 99%

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

Egnell¹,

Houston²,

Boyer³

2003

J Pharmacol Exp Ther

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Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4 substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could give rise to increased drug clearance. To test the possible in vivo relevance of atypical cytochrome P450 kinetics, we investigated the role of heteroactivation in the therapeutically relevant drug interaction between the anti-epileptics felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in vivo concentrations of both drugs (maximum activation 98% at 10 M carbamazepine, 1 mM felbamate). Felbamate (50 -500 M) did not induce CYP3A4, as based on mRNA measurements in human liver slices. The further metabolism of carbamazepine-ep was inhibited (38% by 500 M felbamate) in human liver slices. We propose a methodology to predict changes in steady-state plasma concentrations (Css) of parent drug and metabolite from in vitro heteroactivation and inhibition data, including prediction of the increase in fraction metabolized. A meta-analysis of reported in vivo effects of felbamate on Css carbamazepine was performed to allow evaluation of this approach. The predicted effect of in vitro heteroactivation on Css carbamazepine corresponds well to that observed in vivo. Combining the effect of heteroactivation on the fraction metabolized to carbamazepineep, and inhibition of its further metabolism, predicts a change in Css carbamazepine-ep that falls within the range observed in vivo. Our results strongly suggest that in vivo heteroactivation of CYP3A4 is a possible mechanism of the clinically observed drug interaction between felbamate and carbamazepine.Estimations of in vivo clearance and drug interaction risk of investigational drugs is commonly achieved by extrapolation from in vitro measurements of cytochrome P450 (P450) activity (Houston, 1994;Ito et al., 1998). The generally acknowledged prediction methodology is based on the assumption that P450-mediated reactions follow simple MichaelisMenten kinetics. However, extensive in vitro evidence suggest that CYP3A4, the most abundant hepatic P450 involved in the metabolism of a majority of drugs (Benet et al., 1996a;Thummel and Wilkinson, 1998) does not always display Michaelis-Menten kinetics. The atypical kinetics observed with CYP3A4 include sigmoidal saturation curves (autoactivation), activation by effectors (heteroactivation), marker substrate-dependent effects on estimations of K i values, nonmutual inhibition between substrates, and simultaneous metabolism of two different substrates without competitive inhibition (Shou et al

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Section: Methodsmentioning

confidence: 99%

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

Egnell¹,

Houston²,

Boyer³

2003

J Pharmacol Exp Ther

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“…Comedication with CBZ results in up to eightfold increases in epoxide concentrations and frequently results in clinical toxicity (80,81). Although valpromide has been used interchangeably with VPA, caution must be exercised if patients also are being treated with CBZ.…”

Section: Carbamazepine Coadministered With Valproatementioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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“…Results and discussion Previous attempts to define the effect of VPA and its amide analogue (valpromide) on epoxide elimination have relied upon the administration of a single oral dose of epoxide in healthy volunteers (Kerr et al, 1989;Pisani et al, 1988 CBZ which need not be administered per se in order to characterize its disposition. The extensive metabolism of epoxide to its trans-dihydrodiol metabolite and subsequent elimination of this terminal metabolite in the urine suggest that epoxide formation and elimination can be characterized from plasma and urinary data (Eichelbaum et al, 1985).…”

Section: Theoretical Considerationsmentioning

confidence: 99%

Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.

Robbins

Wedlund

Kuhn

et al. 1990

Brit J Clinical Pharma

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The effect of valproic acid (VPA) on the disposition of carbamazepine-10,11-epoxide (epoxide) was studied in five epileptic patients on chronic carbamazepine (CBZ) therapy. The individual pharmacokinetic parameters influencing epoxide disposition were determined in the presence and absence of VPA. VPA significantly decreased the clearance of unbound epoxide (an in vivo index of epoxide hydrolase activity), but did not appear to affect epoxide formation. VPA also increased the free concentrations of both CBZ and epoxide.

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Effect of valpromide on the pharmacokinetics of carbamazepine‐10, 11‐ epoxide.

Cited by 23 publications

References 12 publications

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

The Importance of Drug Interactions in Epilepsy Therapy

Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.

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