Metabolism and excretion of mood stabilizers and new anticonvulsants

Terence A. Ketter, Mark A Frye, Gabriela Corá-Locatelli, Timothy A. Kimbrell, Robert M. Post

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)511-532
Number of pages22
JournalCellular and Molecular Neurobiology
Volume19
Issue number4
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Drug interactions
Metabolism
Anticonvulsants
Drug Interactions
Pharmaceutical Preparations
Valproic Acid
Enzyme inhibition
zonisamide
Pharmacokinetics
felbamate
Carbamazepine
Lithium
Toxicity
Vigabatrin
Epoxide Hydrolases
Aptitude
Liver
Epoxy Compounds
Phenytoin
Phenobarbital

Keywords

  • Anticonvulsants
  • Bipolar disorder
  • Carbamazepine
  • Drug-drug interactions
  • Excretion
  • Felbamate
  • Gabapen tin
  • Lamotrigine
  • Lithium
  • Metabolism
  • Mood disorders
  • Mood stabilizers
  • Tiagabine
  • Topiramate
  • Valproate

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Biochemistry
  • Cell Biology
  • Genetics

Cite this

Metabolism and excretion of mood stabilizers and new anticonvulsants. / Ketter, Terence A.; Frye, Mark A; Corá-Locatelli, Gabriela; Kimbrell, Timothy A.; Post, Robert M.

In: Cellular and Molecular Neurobiology, Vol. 19, No. 4, 1999, p. 511-532.

Research output: Contribution to journalArticle

Ketter, Terence A. ; Frye, Mark A ; Corá-Locatelli, Gabriela ; Kimbrell, Timothy A. ; Post, Robert M. / Metabolism and excretion of mood stabilizers and new anticonvulsants. In: Cellular and Molecular Neurobiology. 1999 ; Vol. 19, No. 4. pp. 511-532.
@article{bca0d174e5cd4e99a9508f61565ad56c,
title = "Metabolism and excretion of mood stabilizers and new anticonvulsants",
abstract = "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.",
keywords = "Anticonvulsants, Bipolar disorder, Carbamazepine, Drug-drug interactions, Excretion, Felbamate, Gabapen tin, Lamotrigine, Lithium, Metabolism, Mood disorders, Mood stabilizers, Tiagabine, Topiramate, Valproate",
author = "Ketter, {Terence A.} and Frye, {Mark A} and Gabriela Cor{\'a}-Locatelli and Kimbrell, {Timothy A.} and Post, {Robert M.}",
year = "1999",
doi = "10.1023/A:1006990925122",
language = "English (US)",
volume = "19",
pages = "511--532",
journal = "Cellular and Molecular Neurobiology",
issn = "0272-4340",
publisher = "Springer New York",
number = "4",

}

TY - JOUR

T1 - Metabolism and excretion of mood stabilizers and new anticonvulsants

AU - Ketter, Terence A.

AU - Frye, Mark A

AU - Corá-Locatelli, Gabriela

AU - Kimbrell, Timothy A.

AU - Post, Robert M.

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - Anticonvulsants

KW - Bipolar disorder

KW - Carbamazepine

KW - Drug-drug interactions

KW - Excretion

KW - Felbamate

KW - Gabapen tin

KW - Lamotrigine

KW - Lithium

KW - Metabolism

KW - Mood disorders

KW - Mood stabilizers

KW - Tiagabine

KW - Topiramate

KW - Valproate

UR - http://www.scopus.com/inward/record.url?scp=0033049627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033049627&partnerID=8YFLogxK

U2 - 10.1023/A:1006990925122

DO - 10.1023/A:1006990925122

M3 - Article

C2 - 10379423

AN - SCOPUS:0033049627

VL - 19

SP - 511

EP - 532

JO - Cellular and Molecular Neurobiology

JF - Cellular and Molecular Neurobiology

SN - 0272-4340

IS - 4

ER -