Effect of Felbamate on Plasma Levels of Carbamazepine and Its Metabolites

Albani, Fiorenzo; Theodore, William H.; Washington, Patricia M.; Devinsky, Orrin; Bromfield, Edward B; Porter, Roger J.; Nice, Frank J.

doi:10.1111/j.1528-1157.1991.tb05624.x

Cited by 71 publications

(25 citation statements)

References 3 publications

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“…3, A, B, and E) and rCYP3A4 (Fig. 3, C (Wilensky et al, 1985;Graves et al, 1989;Theodore et al, 1989;Albani et al, 1991;Theodore et al, 1991;Wagner et al, 1993). Heteroactivation is most evident at low substrate concentrations, resulting in a doubling in activity when combining the highest felbamate concentration (1 mM) and the lowest carbamazepine concentration (10 M).…”

Section: Resultsmentioning

confidence: 99%

“…Instead it was assumed that the low clearance of carbamazepine-ep (Benet et al, 1996b) allows the approximation that CLtot CBZ-ep is independent of hepatic blood flow and proportional to in vitro CLf CBZ-diol ϫ fu plasma . Since fu plasma is not changed by felbamate (Albani et al, 1991), the in vivo ratio of CLtot CBZ-ep control /CLtot CBZ-ep FBM was quantitatively estimated from the ratio of the amount of carbamazepine-diol formed in human liver slices in the absence or presence of felbamate.…”

Section: Cyp3a4 Heteroactivation Associated With Drug Interaction 1253mentioning

confidence: 99%

“…Felbamate is a weak inducer of rat P450s, and no evidence for induction of human P450s has been reported (Segelman et al, 1985;Swinyard et al, 1987). Plasma protein binding displacement of carbamazepine by felbamate (fraction unbound of felbamate: 0.75) could be excluded based on literature (Albani et al, 1991;Benet et al, 1996b). The in vivo effect has been quantified in several independent studies in human, allowing for evaluation of in vitro based predictions.…”

mentioning

confidence: 99%

“…Addition of felbamate to carbamazepine monotherapy results in a decrease in carbamazepine plasma concentrations and a concomitant increase in the plasma concentration of the P450-mediated metabolite carbamazepine-10,11-epoxide (carbamazepine-ep) (Graves et al, 1989;Albani et al, 1991;Theodore et al, 1991;Wagner et al, 1993). This drug interaction was chosen for our study because it fulfills some important criteria for testing the hypothesis of in vivo heteroactivation.…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Cyp3a4 Heteroactivation Associated With Drug Interaction 1253mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…In humans, a weak increase (10%) in apparent oral clearance of the CYP2C9 substrate flurbiprofen was observed after 7 days of treatment with dapsone, a heteroactivator of flurbiprofen in vitro (Hutzler et al, 2001). Finally, a clinically observed drug-drug interaction between felbamate and carbamazepine, causing a decrease in steadystate concentrations of carbamazepine (Albani et al, 1991), has been shown to be quantitatively predicted from in vitro human liver microsomal data (Egnell et al, 2003b).…”

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confidence: 99%

Predictive Models of CYP3A4 Heteroactivation: In Vitro-in Vivo Scaling and Pharmacophore Modeling

Egnell

Houston²,

Boyer³

2004

J Pharmacol Exp Ther

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Although activation of CYP3A4 is frequently observed in vitro, predictive computational-based models and methods for in vitro-in vivo scaling are scarce. It has been previously shown that in vitro CYP3A4 heteroactivation of carbamazepine (CBZ)-epoxide (ep) formation can be associated with the clinical drug interaction between felbatame and CBZ. The previously reported prediction methodology is applied here to an additional set of in vitro CYP3A4 heteroactivators, some exerting this effect at concentrations relevant in vivo. The antimalarial artemisinin potently increases CBZ-ep formation by a maximum of 500% at 300 M. Testosterone and progesterone activates by a maximum of 1680 and 920%, respectively, at 150 M, and quinidine causes a 130% increase at 300 M. The predicted maximum in vivo decrease in steady-state concentration of carbamazepine (Css CBZ ) at saturating effector concentrations is 85 to 90% for testosterone and progesterone, 75% for artemisinin, and 45% for quinidine. The corresponding predicted in vivo increase in Css CBZ-ep is 50, 60, 55, and 30% for artemisinin, testosterone, progesterone, and quinidine, respectively. At effector concentrations relevant in vivo, the Css CBZ change is predicted to Յ20% for testosterone, artemisinin, and quinidine and Յ10% for progesterone, with a concomitant Css CBZ-ep increase of 12% for testosterone and Յ10% for progesterone, artemisinin, and quinidine. Structure-heteroactivation relationships were evaluated by generating a pharmacophore. The model includes two hydrogen bond acceptor features separated by hydrophobic features. Internal predictivity is high, and heteroactivation of an external test set correlate to observed in vitro heteroactivation.Inhibition of cytochromes P450 is a well known phenomena in vitro and has been shown to translate to decreases in P450-mediated metabolism in vivo, sometimes leading to clinically relevant drug-drug interactions (Lin and Lu, 1998). Quantitative prediction of the in vivo relevance of P450 inhibition based on in vitro data has also become an integral part of drug discovery and is based on methods that are continuously validated by comparison with in vivo observations (Ito et al., 2004). An increased number of attempts have also been made at producing computational models of P450 inhibition (Afzelius et al., 2001;Ekins et al., 2001).Extensive observations, however, suggest that apart from inhibition, modulation of cytochromes P450 can also occur by activation, a phenomenon that if translated to in vivo events is also a potential source of drug-drug interactions. The in vivo effects of P450 heteroactivation would be observed as an increased clearance of the affected drug, similar to the changes observed by P450 induction, except that the time course of the interaction would not be determined by the rate of synthesis and turnover of P450 enzyme but by the halflives of the interacting drugs. Activation of CYP3A4 has been extensively studied in vitro and based on site-directed mutagenesis studies (Khan et al., 2002), ...

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Felbamate

Leppik¹

2004

The Treatment of Epilepsy

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Effect of Felbamate on Plasma Levels of Carbamazepine and Its Metabolites

Cited by 71 publications

References 3 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

Predictive Models of CYP3A4 Heteroactivation: In Vitro-in Vivo Scaling and Pharmacophore Modeling

Felbamate

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