Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy.
Free and total carbamazepine (CBZ) and carbamazepine-epoxide (CBZ-EP) plasma levels were obtained on 113 patients with epilepsy (18-61 years old) controlled on either monotherapy or coadministration with either phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), or all three. A subset of patients were administered tetradeuterium labeled CBZ to evaluate the effects of autoinduction and coadministration of VPA on the kinetics of CBZ and its metabolite CBZ-EP. Polytherapy had variable effect on free and total CBZ plasma levels compared to monotherapy. Coadministered PHT (co-PHT), or all three anticonvulsants together (PHT, PB, and VPA: co-AEDs) decreased free and total CBZ plasma levels. No change was noted for coadministered VPA (co-VPA). Compared to monotherapy the free and total CBZ-EP levels increased with co-VPA, less with coadministered PB (co-PB), and no change with co-PHT or co-AEDs. Protein binding of CBZ and CBZ-EP was not affected by any antiepileptic drugs studied. The free and total CBZ-EP/CBZ ratio was tripled with co-VPA or co-AED's, and doubled with co-PHT or co-PB. Isotope labeling did not demonstrate any differences in half-life (t1/2), plasma clearance (Cl), or volume of distribution (Vd). Compared to naive controls, monotherapy and co-VPA decreased CBZ t1/2 by 50%, and more than doubled the CBZ Cl without a significant change in the Vd. Autoinduction is one explanation for these changes with chronic CBZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Ramsay
R E
RE
Department of Neurology, University of Miami, Florida 33136.
McManus
D Q
DQ
Guterman
A
A
Briggle
T V
TV
Vazquez
D
D
Perchalski
R
R
Yost
R A
RA
Wong
P
P
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000008:administration & dosage* / Q000627:therapeutic use; D010672:Phenytoin / Q000008:administration & dosage* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D014635:Valproic Acid / Q000008:administration & dosage* / Q000627:therapeutic use
D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; C012227:carbamazepine epoxide; D010634:Phenobarbital