Metabolism and excretion of mood stabilizers and new anticonvulsants

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California 94305-5723, USA.
Cellular and Molecular Neurobiology (Impact Factor: 2.51). 09/1999; 19(4):511-32. DOI: 10.1023/A:1006990925122
Source: PubMed


1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

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    • "lamotrigine, tiagabine, benzodiazepines and barbiturates exhibit substantial degrees of binding to plasma proteins [9] [49]. On the other hand, several agents do not exhibit any appreciable protein binding, including ethosuximide, gabapentin, levetiracetam, primidone, topiramate, and vigabatrin [13] [14] [15]. There are several important classes of plasma binding proteins, the most notable being albumin and glycoproteins. "
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    ABSTRACT: Individual differences in clinical responsiveness to antiepileptic drugs are due to a complex interaction between environmental factors and genetic variation. Considerable interest has arisen in exploiting advances in molecular genetics to improve drug therapy for epilepsy and many other diseases; however, practical application of pharmacogenetics has been difficult to realize. Attempts to define gene variants that are associated with therapeutic (or adverse) effects of antiepileptic drugs rely currently on the prior identification of candidate genes and the subsequent evaluation of the distribution of allelic variants between individuals who have a "good" versus a "poor" clinical response. Many factors can adversely affect interpretation of such data, and careful consideration must be given to the design of genetic association studies involving candidate genes. Candidate genes may be identified in a number of ways; however, for studies of drugs, application of knowledge derived from basic pharmacology can suggest focused and testable hypotheses that are based on the fundamental principles of drug action. Thus, studies of genetic variation as they relate to proteins involved in antiepileptic drug kinetics and dynamics will identify key polymorphisms in endogenous molecules that determine degrees of drug efficacy and toxicity. Delineation of these effects in the coming years will promote enhanced success in the treatment of epilepsy.
    Epilepsy & Behavior 09/2005; 7(1):18-36. DOI:10.1016/j.yebeh.2005.04.010 · 2.26 Impact Factor
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    • "The D 2(E) –VPA metabolite is a more potent anticonvulsant and remains in the brain longer than VPA in rodent models [36]; however even with these characteristics it is questionable whether the levels of this metabolite within the CNS are enough to produce therapeutic benefit. VPA also undergoes a variety of oxidation reactions within the endoplasmic reticulum (ER) to produce a variety of metabolites (reviewed in [20]), including (1) hydroxylation products arising from cytochrome P450 metabolism (3-OH-VPA, 4-OH-VPA, 5-OH-VPA), (2) ketones arising from the oxidation of 3-OH-VPA or 4-OH-VPA (3-oxo- VPA, 4-oxo-VPA), and (3) dicarboxylic acids arising from oxidation of 4-OH-VPA and 5-OH-VPA (propylglutaric acid, propylsuccinic acid). A small proportion of VPA (0.3%) undergoes cytochrome P450 desaturation in liver microsomes to produce D "
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    ABSTRACT: Bipolar disorder (BPD) affects approximately 1% of the population worldwide (Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. J Am Med Assoc 1996;276:293–99, [1]) and is a debilitating illness associated with high morbidity and mortality (10% lifetime risk of suicide). Valproic acid (VPA) is a widely used alternative to lithium salts for the treatment of BPD, and has been in clinical use for epilepsy for years, but its mechanism of action has not been defined in any setting. A large number of indirect targets as well as a more limited number of direct in vitro targets for VPA have been described, but strong evidence that these targets play a role in the therapeutic response is lacking. VPA was recently shown to inhibit histone deacetylases (HDACs), key regulators of chromatin structure and transcription. In this review we summarize the history and pharmacology of VPA and address the potential role of HDACs in the response to VPA. Review of these studies suggests that inhibition of HDACs is a highly plausible mechanism for VPA-mediated cellular differentiation and teratogenesis, but cannot account for the anticonvulsant and mood regulating actions of VPA that more likely involve different or additional targets.
    Clinical Neuroscience Research 12/2004; 4(3-4-4):215-225. DOI:10.1016/j.cnr.2004.09.013 · 0.80 Impact Factor
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    • "The peak of absorbtion after a single oral dose is 6 –24 h, the bioavailability is 58–87 %, and the protein binding is 70 –80 %. After 2–3 wk of treatment, the plasma levels may drop by 20 –30 %, because carbamazepine auto-induces its own metabolism through the induction of the cytochrome P450 hepatic system (isoform CYP 3A3\4) (Kerr et al., 1994 ; Ketter et al., 1999). Its most important metabolite, the 10,11- epoxide-carbamazepine, also has anticonvulsant properties, and is excreted by the urine, as well as carbamazepine (Bertilsson and Tomson, 1986). "
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    ABSTRACT: The authors reviewed the available literature on the efficacy of carbamazepine, valproate, and other newer anticonvulsants for the treatment of bipolar disorder. A comprehensive Medline search was conducted, and all uncontrolled and controlled reports on anticonvulsants used for the treatment of bipolar patients were identified. Carbamazepine and valproate have been shown to be effective in the acute treatment of bipolar disorder, and are the first-choice treatments for lithium-refractory patients. While the efficacy of these drugs in the acute treatment of the illness has been satisfactorily documented, double-blind randomized studies are still necessary to evaluate the long-term effectiveness of both anticonvulsants. Patients on a mixed state and rapid cyclers seem to respond better to valproate and carbamazepine than to lithium. The preliminary data evaluating the efficacy of newer anticonvulsants, such as gabapentin, lamotrigine, and topiramate in bipolar patients is still limited, but some of the available findings are promising, and these new agents may represent appropriate third choices for refractory bipolar individuals. Double-blind, controlled studies with the newer anticonvulsants are still largely unavailable, and it will be necessary to evaluate their acute and prophylactic mood-stabilizing effects. The prospects for future therapeutic advances in this area are also discussed.
    The International Journal of Neuropsychopharmacology 12/2002; 4(4):421-46. DOI:10.1017/S1461145701002668 · 4.01 Impact Factor
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