Relationships Between Carbamazepine-Diol, Carbamazepine-Epoxide, and Carbamazepine Total and Free Steady-State Concentrations in Epileptic Patients: The Influence of Age, Sex, and Comedication

Da, Svinarov; Ce, Pippenger

doi:10.1097/00007691-199612000-00006

Cited by 21 publications

(13 citation statements)

References 28 publications

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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%

“…CYP2C8-mediated epoxidation also occurs, but to a much lesser extent. Carbamazepine 10,11-epoxide is subsequently converted to carbamazepine 10,11-trans-diol by epoxide hydrolase and excreted in the urine (Svinarov and Pippenger, 1996). Thus, any alteration of the CYP3A-mediated metabolic pathway has a significant impact on the clearance of carbamazepine.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

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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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“…. Although the CBZ dose-serum concentration relationship is complicated, serum concentrations are still being used clinically either to assess the dose titration or to monitor potential toxicity. Several factors are known to influence the relationship between dose and steady-state level of CBZ including age, gender, genetic differences, weight, variability in absorption, dose-dependent auto induction, disease states and concomitant medication (29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Carbamazepine in Indian Epileptic Patients

Perumandla

Shesham

Devarakonda

2005

Clinical Research and Regulatory Affairs

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ⅪThe aim of this study was to describe the population pharmacokinetics of carbamazepine in Indian epileptic patient population. The covariates evaluated were total body weight, height, age, dose, and gender. A total of 307 steady state serum concentrations were collected from 84 patients and analyzed. Population pharmacokinetic parameters were calculated using NONMEM, with one compartment first order absorption and elimination. The absorption rate was set at a fixed value of 1.2 h -1 . Exponential interindividual error and additive residual error model were developed. The model that was found to best describe the data following FO method was: Apparent Clearance (CL/F) (L/h)= 0.785 + 1.16 * (TBW/41.2) ** 0.75 * EXP (0.0976); Apparent Volume (V/F) (L) = 24.8 + 21.4 *(TBW/41.2)* EXP (0.740). Similarly the model found to best describe the data following FOCE method was CL/F (L/h) = 0.632 + 1.63 * (TBW/41.2) ** 0.75 * EXP (2.35E-12); V/F (L) = 31.8 + 56.9 *(TBW/41.2)* EXP (0.180).The final model estimates of CL/F and V/F estimated by FO method were 0.05 L/h/kg and 1.7 L/kg respectively and by FOCE method are 0.043 L/h/kg 1.43L/kg respectively. The typical body weight used for this population was 40 kg.

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“…In humans, CBZ is converted to its major metabolite CBZ-e, predominantly in the liver, by cytochrome p450 3A (16). CBZ and CBZ-e exhibit similar pharmacological activity, and plasma CBZ-e levels reach roughly one-half of CBZ levels (17), thus making the simultaneous control of CBZ and CBZ-e levels desirable. CBZ induces its own metabolism (18), whereas other drugs can either induce or inhibit CBZ metabolism (19,20).…”

Section: Introductionmentioning

confidence: 99%

Quantitative dynamic nuclear polarization‐NMR on blood plasma for assays of drug metabolism

Lerche¹,

Meier

Jensen³

et al. 2010

NMR in Biomedicine

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Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear polarization-NMR (DNP-NMR) in the form of the hyperpolarization-dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid-state NMR transients. This study explores the capability of quantitative in vitro DNP-NMR to assay drug metabolites in blood plasma. The lower limit of detection for the anti-epileptic drug (13)C-carbamazepine and its pharmacologically active metabolite (13)C-carbamazepine-10,11-epoxide is 0.08 µg/mL in rabbit blood plasma analyzed by single-scan (13)C DNP-NMR. An internal standard is used for the accurate quantification of drug and metabolite. Comparison of quantitative DNP-NMR data with an established analytical method (liquid chromatography-mass spectrometry) yields a Pearson correlation coefficient r of 0.99. Notably, all DNP-NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP-NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring.

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Relationships Between Carbamazepine-Diol, Carbamazepine-Epoxide, and Carbamazepine Total and Free Steady-State Concentrations in Epileptic Patients: The Influence of Age, Sex, and Comedication

Cited by 21 publications

References 28 publications

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

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

Population Pharmacokinetics of Carbamazepine in Indian Epileptic Patients

Quantitative dynamic nuclear polarization‐NMR on blood plasma for assays of drug metabolism

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