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

Egnell, Ann-Charlotte; Houston, B.; Boyer, Scott

doi:10.1124/jpet.102.047530

Cited by 67 publications

(56 citation statements)

References 36 publications

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“…Cooperativity can occur between ligands of the same (homotropic) or different (heterotropic) molecular species, leading to stimulation or inhibition of catalytic activity. Unfortunately, these interactions are not well understood [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Energetics of heterotropic cooperativity between α-naphthoflavone and testosterone binding to CYP3A4

Roberts¹,

Atkins²

2007

Archives of Biochemistry and Biophysics

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Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of a majority of drugs. Heterotropic cooperativity of drug binding to CYP3A4 was examined with the flavanoid, α-naphthoflavone (ANF) and the steroid, testosterone (TST). UV-vis and EPR spectroscopy of CYP3A4 show that ANF binding to CYP3A4 occurs with apparent negative cooperativity and that there are at least two binding sites: 1) a relatively tight spin-state insensitive binding site (CYP•ANF) and 2) a relatively low affinity spin-state sensitive binding site (CYP•ANF•ANF). Since binding to the spin-state insensitive binding site is considerably tighter for ANF than TST, the spin-state insensitive binding site could be occupied by ANF, while titrating TST at the other site(s).

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Section: Introductionmentioning

confidence: 99%

Energetics of heterotropic cooperativity between α-naphthoflavone and testosterone binding to CYP3A4

Roberts¹,

Atkins²

2007

Archives of Biochemistry and Biophysics

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Section: Brain Peripheral P450 and Drug Metabolism: Focus On Aedsmentioning

confidence: 99%

“…Generally, first generation AEDs differ substantially from second generation AEDs in terms of metabolic transformation pathways (Phase I and II) and drug-to-drug interactions [9,37,42,43]. For example, carbamazepine (first generation AED) is a substrate and an inducer of hepatic CYP3A4 [26,[38][39][40]44] while phenytoin serum levels are determined by CYP2C9 and CYP2C19 [38,44,45].…”

Section: Brain Peripheral P450 and Drug Metabolism: Focus On Aedsmentioning

confidence: 99%

“…In particular, P450 phase I enzymes (e.g., CYP3A4/5 and CYP2C9/19) are responsible for the hepatic metabolism of first generation AEDs and some second generation ones [26,[37][38][39][40]. Phase II enzymes such as glutathione-S-transferase (GSTs), sulfotransferase and UDP-glucuronosyl-transferase (UGTs) are responsible for the metabolic clearance of both first and second generation AEDs [41].Generally, first generation AEDs differ substantially from second generation AEDs in terms of metabolic transformation pathways (Phase I and II) and drug-to-drug interactions [9,37,42,43] . Both first and second generation AED undergo Phase II metabolism.…”

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confidence: 99%

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Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Ghosh¹

2011

CDM

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Drug penetration into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Even though a number of strategies to circumvent the BBB and to improve drug access have been developed, drug resistance in CNS diseases remains an unmet clinical problem. We here review the mechanisms by which a healthy or pathological BBB influences drug distribution in the brain, with emphasis on the role of P450 metabolic enzymes and multi-drug transporter (MDT) proteins. In addition to the classic hepatic and gut biotransformation pathways, CNS expression of P450 enzymes may bear pharmacokinetic and pharmacodynamic significance exerting a metabolic activity and transforming parent drugs into specific products. We propose these mechanisms to play a major role in CNS drug resistant pathologies including refractory forms of epilepsy.Changes in the cerebrovascular hemodynamic conditions can affect expression of P450 enzymes and MDT proteins. This should be taken into account when developing in vitro experimental approaches to reproduce the physiological or pathological properties of the BBB. Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed. KeywordsBlood-brain barrier; drug resistant epilepsy; multidrug transporters proteins (MDT); P450 enzymes THE BLOOD-BRAIN BARRIER: A BRIEF OVERVIEWThe brain microvascular endothelial cells that constitute the blood-brain barrier (BBB) are responsible for the passage of xenobiotics and nutrients from the blood into the brain parenchyma, and vice versa. At the cellular level, the BBB consists of endothelial cells HHS Public Access DRUG RESISTANCE IN CNS DISEASESDrug resistance in brain diseases is an unsolved clinical problem. For example, drug resistant epilepsy affects approximately 20-25% of epileptics. According to the recent consensus of the International League Against Epilepsy (ILAE), "drug resistant epilepsy is defined with the failure of adequate trials of two appropriately chosen antiepileptic drugs, whether as monotherapies or in combination, to achieve sustained seizure freedom" [7]. In the past two decades, new antiepileptic drugs (AEDs) have been developed but no major reduction in the percentage of drug-resistant patients has been achieved [8,9]. The complexity of the drug resistant epileptic phenotype reflects the nature of the pathophysiological process, its possible evolution over time and individual sensitivity to drugs. In order to explain the mechanisms underlying the drug resistant condition, a pharmacokinetic and a pharmacodynamic hypothesis were proposed more than a decade ago. AED therapeutic failure may thus be due to a modification of neuronal targets (pharmacodynamic hypothesis) [10][11][12][13] or to inadequate AED brain levels (pharmacokinetic hypothesis). Overexpression of multidrug transporter (MDTs) proteins at the BBB was considered to be a mechanism responsible for the possible AED brain misdistribution [11,[14][15][16][17][18]: overexpression of multi-drug transporters at the BBB...

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“…22) Taking these findings together, it can be speculated that endogenous compounds might be activating the sigmoidal metabolism of drugs in vivo, causing the discrepancy of clearance parameters between in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Prediction of <i>in Vivo</i> Carbamazepine 10,11-Epoxidation from <i>in Vitro</i> Metabolic Studies with Human Liver Microsomes: Importance of Its Sigmoidal Kinetics

Sakamoto

Itoh

Fujiwara

2013

Biological & Pharmaceutical Bulletin

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Hepatic intrinsic clearance (CL int ) of drugs is often predicted based on in vitro data that are obtained from the Michaelis-Menten analysis. While most of the metabolic rate-substrate concentration kinetic curves fit to the Michaelis-Menten equation, cytochrome P450 (CYP) and uridine 5′-diphosphate (UDP)-glucuronosyltransferases exhibit sigmoidal kinetics for certain drugs. In our study, the kinetics of CYP3A4-catalyzed carbamazepine 10,11-epoxidation in human liver microsomes was sigmoidal and fitted to the Hill equation, revealing the S 50 value of 358 µM, n of 2.0, and the V max value of 463 pmol/min/mg. While the intrinsic clearance calculated from Michaelis-Menten parameters (CL int ) overestimated the observed in vivo intrinsic clearance (CL int, in vivo ), the maximum intrinsic clearance calculated based on the Hill equation (CL max ) exhibited better predictions of CL int, in vivo . Such better prediction using the CL max was also observed for other four drugs, all of which also exhibited sigmoidal metabolic rate-concentration curves, according to the literature data. However, even if we assume such Hill equation, intrinsic clearances predicted at their therapeutic concentrations from in vitro data were still much lower than their CL int, in vivo , suggesting the existence of unknown factors causing discrepancy between in vitro intrinsic clearance in human liver microsomes and in vivo data. Thus, even if we assume sigmoidal kinetics, that would not be enough for accurate prediction of CL int, in vivo , and it would be preferable to use CL max to quantitatively extrapolate the in vitro data to in vivo clearance. Key words carbamazepine metabolism; sigmoidal kinetics; in vitro-in vivo extrapolation; cytochrome P450 3A4One of the ultimate goals of in vitro drug metabolism research is the prediction of in vivo clearance of drugs from in vitro data. Phase I and II drug-metabolizing enzymes such as cytochrome P450 (CYP) and uridine 5′-diphosphate (UDP)-glucuronosyltransferases (UGT) metabolize drugs to generate metabolites, which are generally pharmacologically inactive and more hydrophilic than the parent compounds, and are therefore easily excreted from the body through the kidney or the liver.1,2) Since these metabolic processes play a central role in the clearance of drugs, the metabolic clearance of drugs, which is commonly described as an intrinsic clearance (CL intoften estimated as the ratio of V max to K m ), is calculated from in vitro research to estimate the in vivo clearance of the drugs. 3)Carbamazepine (5-carbamoyl-5H-dibenz-[b,f ] azepine) is a widely used anti-epileptic drug, and the first-line drug of choice in partial epilepsy. Since its increased concentration in the blood is tightly linked to the onset of adverse effects of carbamazepine including drug addiction, the blood levels of carbamazepine are monitored so as not to exceed the therapeutic range, which is normally 4-12 µg/mL. 4) Carbamazepine is metabolized to over 30 metabolites in humans such as carbamazepine 10,11-epoxide, 2-and...

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

Cited by 67 publications

References 36 publications

Energetics of heterotropic cooperativity between α-naphthoflavone and testosterone binding to CYP3A4

Energetics of heterotropic cooperativity between α-naphthoflavone and testosterone binding to CYP3A4

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Prediction of <i>in Vivo</i> Carbamazepine 10,11-Epoxidation from <i>in Vitro</i> Metabolic Studies with Human Liver Microsomes: Importance of Its Sigmoidal Kinetics

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