Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid

Levy, René H.; Rettenmeier, Albert W.; Anderson, Gail D.; Wilensky, Alan J.; Friel, Patrick N.; Baillie, Thomas A.; Acheampong, Andrew; Tor, Jacques; Guyot, M.; Loiseau, P

doi:10.1038/clpt.1990.144

Cited by 115 publications

(60 citation statements)

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“…Although 4-ene-VPA has been implicated as a putative hepatotoxin (18), the significance of its apparent increased formation in patients on concomitant TPM therapy is unclear. In earlier studies, VPA glucuronidation and 4-ene-VPA formation were shown to increase with increasing doses of VPA (34) and in patients receiving polytherapy with p,,, inducers (1 8).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Rosenfeld

Liao²,

Kramer³

et al. 1997

Epilepsia

112

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Summary:Purpose: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions.Methods: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy.Results: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for 2 2 weeks without VPA. TPM plasma peak concentration (Cmax) and area under the concentration-versus-time curve during a 12-h dosing interval (AUC,,,) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy.

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Section: Discussionmentioning

confidence: 99%

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Rosenfeld

Liao²,

Kramer³

et al. 1997

Epilepsia

112

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“…Its major metabolic pathways are glucuronidation and mitochondrial b-oxidation, while CYP-dependent oxidation is only a minor pathway [15]. The steady-state plasma concentrations of the metabolites are at least 100-fold lower than those of the parent compound [16]. Thus, it is unlikely that the metabolites would signi®cantly alter CYP-dependent drug metabolism in vivo.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

Xia

Wang

Kivistö

et al. 2001

Brit J Clinical Pharma

141

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Aims To evaluate the potency and speci®city of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. Methods Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform speci®c marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4k-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1k-hydroxylase (CYP3A4). Results Valproic acid competitively inhibited CYP2C9 activity with a K i value of 600 mM. In addition, valproic acid slightly inhibited CYP2C19 activity (K i =8553 mM, mixed inhibition) and CYP3A4 activity (K i =7975 mM, competitive inhibition).The inhibition of CYP2A6 activity by valproic acid was time-, concentration-and), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. Conclusions Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in signi®cant drug interactions.

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“…In addition, Phase II biotrans-formation could further shape the levels of brain AEDs. The drug resistant brain could represent a second line of drug biotransformation, significantly changing the pharmacokinetic and pharmacodynamic properties of brain drugs, such as AEDs.An obvious confounding factor is represented by drug-to-drug interactions, especially in patients receiving multi-therapies or undergoing several drug rotations [9,[50][51][52][53][54][55][56]. A recent review article examined the up-to-date information on drug interactions in epilepsy therapy.…”

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confidence: 99%

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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Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid

Cited by 115 publications

References 10 publications

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

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

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