Carbamazepine but not valproate induces bupropion metabolism.
Bupropion (BUP) may be less likely than other antidepressants to cause switches into mania and rapid cycling, suggesting utility in bipolar disorder. The combination of BUP with the mood-stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) is a strategy that might further lessen the risk of mania. CBZ induces, and to a lesser extent VPA inhibits the hepatic metabolism of various medications, but their effects on BUP have not been previously studied. Inpatients with mood disorders had pharmacokinetic profiles of BUP and metabolites assessed after single, oral, 150-mg doses of BUP while receiving placebo (N = 17) or during chronic blind CBZ (N = 12) or VPA (N = 5) monotherapy. CBZ but not VPA therapy decreased BUP peak concentrations (Cmax) by 87% (p < 0.0001) and 24-h area under the curve (AUC) by 90% (p < 0.0001), threohydrobupropion Cmax by 81% (p <0.0009) and AUC by 86% (p < 0.002), and erythropydrobupropion Cmax by 86% (p < 0.05) and AUC by 96% (p < 0.05). CBZ increased hydroxybupropion (H-BUP) Cmax by 71% (p < 0.007) and AUC by 50% (p < 0.09) and H-BUP AUC by 94% (p < 0.02). Thus, CBZ markedly decreased BUP and increased H-BUP concentrations, whereas VPA did not affect BUP but increased H-BUP concentrations. Further studies are required to determine how these differential effects of CBZ and VPA on BUP pharmacokinetics influence the tolerability and efficacy of combination therapies with these agents.
Ketter
T A
TA
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
Jenkins
J B
JB
Schroeder
D H
DH
Pazzaglia
P J
PJ
Marangell
L B
LB
George
M S
MS
Callahan
A M
AM
Hinton
M L
ML
Chao
J
J
Post
R M
RM
D000328:Adult; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy*; D016642:Bupropion / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D016896:Treatment Outcome; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000928:Antidepressive Agents; D016642:Bupropion; D002220:Carbamazepine; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A