Pharmacokinetic study of carbamazepine and its epoxide metabolite in humans.

Sumi, Masahiro; Watari, Nobutoshi; Umezawa, Osamu; Kaneniwa, Nobuyoshi

doi:10.1248/bpb1978.10.652

Cited by 15 publications

(17 citation statements)

References 30 publications

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“…The mechanism of the increase in carbamazepine clearance by felbamate is unknown and is in theoretical accordance with the expected effect of in vivo heteroactivation, since the major metabolic pathway (carbamazepine-ep formation) is mediated predominantly by CYP3A4 (Kerr et al, 1994) (Fig. 1), and the fraction of carbamazepine metabolized via carbamazepine-ep, as estimated from a number of clinical reports (Eichelbaum et al, 1985;Sumi et al, 1987;Faigle and Feldmann, 1989;Robbins et al, 1990;Kerr et al, 1994) is high enough to expect heteroactivation of this pathway to yield a measurable change in carbamazepine steadystate plasma concentrations (Css CBZ ). Carbamazepine is a low extraction drug, assuring that in vivo metabolic clearance is dependent on P450 activity with little influence of blood flow.…”

mentioning

confidence: 61%

“…The magnitude of fm control for chronic oral administration was approximated to 0.6, based on calculations from literature data (yielding values of 0.4 -0.7 for single dosing, increasing to up to 0.85 for chronic dosing) (Eichelbaum et al, 1985;Sumi et al, 1987;Faigle and Feldmann, 1989;Robbins et al, 1990;Kerr et al, 1994). The magnitude of fm control was assumed constant over the range of carbamazepine concentrations, regardless of any autoactivation, due to difficulties in assigning which carbamazepine concentration to consider as the control value corresponding to literature fm control .…”

Section: Cyp3a4 Heteroactivation Associated With Drug Interaction 1253mentioning

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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confidence: 61%

Section: Cyp3a4 Heteroactivation Associated With Drug Interaction 1253mentioning

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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“…4). The fm CYP3A4 value of carbamazepine 10,11-epoxidation by CYP3A in vivo was estimated to be 0.4 to 0.8 based on the range of literature reported values (Eichelbaum et al, 1985;Sumi et al, 1987;Svinarov and Pippenger, 1996). Since carbamazepine is a potent inducer of CYP3A4 expression and usually chronically dosed, higher values of fm CYP3A4 (associated with chronic dosing) may be of greater relevance (Eichelbaum et al, 1975(Eichelbaum et al, , 1985.…”

Section: Resultsmentioning

confidence: 99%

“…This metabolic pathway is estimated to be responsible for up to 85% of carbamazepine clearance at steady state (Eichelbaum et al, 1985;Sumi et al, 1987;Svinarov and Pippenger, 1996). CYP2C8-mediated epoxidation also occurs, but to a much lesser extent.…”

Section: Downloaded Frommentioning

confidence: 99%

Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications

Henshall

Galetin²,

Harrison

et al. 2008

Drug Metab Dispos

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ABSTRACT:A systematic analysis of the heteroactivation of CYP3A-mediated carbamazepine 10,11-epoxidation has been investigated in three different in vitro systems, namely recombinant CYP3A4 and CYP3A5, human liver microsomes (HLMs) and cryopreserved human hepatocytes. The effect of 10 endogenous steroids and flavonoids was studied over a range of substrate and effector concentrations. A novel heteroactivation model was used to obtain the parameters EC 200 (concentration of effector required to produce 200% control) and heteroactivation ratio (the ratio of maximum observed reaction velocity to control). The EC 200 values obtained in HLMs and human hepatocytes were corrected for nonspecific binding. Heteroactivation of CYP3A5 has been demonstrated with mean heteroactivation ratios in CYP3A5, HLMs and hepatocytes on average 2-fold greater than in recombinant CYP3A4 for most of the effectors investigated. In recombinant CYP3A4, heteroactivation was greatest at substrate concentrations below K m . Heteroactivation increased with effector concentration in a nonlinear manner and differed between effectors (mean heteroactivation ratios varied up to 12-fold). A greater extent of heteroactivation was observed in HLMs than in human hepatocytes for steroid effectors, but the opposite was true for flavonoid effectors. The observed heteroactivation of CYP3A in intact cells supports an in vivo relevance. From the in vitro heteroactivation data, a significant increase in clearance in vivo was predicted for substrates with a high dependence on CYP3A4 to the overall elimination, indicating that heteroactivation of CYP3A may be a potential source of interindividual variability.Cytochromes P450 (P450s) 3A are the most abundant P450 enzymes in the human liver and small intestine (Paine et al., 2006). In vitro assays of CYP3A-mediated metabolism are used routinely in the drug discovery effort to quantitatively predict in vivo pharmacokinetic parameters. However, these estimates may be confounded by atypical (non-Michaelis-Menten) kinetics such as autoactivation (homotropic cooperativity, evident as a sigmoidal kinetic profile), heteroactivation (heterotropic cooperativity, the activation of a substrate's metabolism by a separate effector compound), or substrate inhibition (inhibition of a substrate's own metabolism) (Houston and Galetin, 2005). A number of studies have addressed the issue of atypical kinetics (Tang and Stearns, 2001;Davydov et al., 2007). Heteroactivation is displayed by a number of CYP3A substrates in vitro, including the antiepileptic, carbamazepine (Nakamura et al., 2002;Egnell et al., 2003a). Heteroactivator-enzyme interaction has been rationalized either by the simultaneous binding of substrate and effector molecules (Shou et al., 1994) or assuming the existence of a separate effector-binding site (Houston and Galetin, 2005).Evidence exists that heteroactivation of CYP3A may occur in vivo. Coadministration of quinidine resulted in an acute increase in diclofenac clearance in monkeys, an effect also observed in m...

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“…Intrinsic formation clearance of carbamazepine-ep formation was calculated by adjusting that under control conditions by the percent activation seen with HLM. The magnitude of fm control for chronic oral administration was approximated to 0.6, based on calculations from literature data (yielding values of 0.4 -0.7 for single dosing, increasing to up to 0.85 for chronic dosing) (Eichelbaum et al, 1985;Sumi et al, 1987;Faigle and Feldmann, 1989;Robbins et al, 1990;Kerr et al, 1994).…”

Section: In Vitro-in Vivo Correlationmentioning

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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Pharmacokinetic study of carbamazepine and its epoxide metabolite in humans.

Cited by 15 publications

References 30 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

Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications

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

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