The influence of polytherapy on the relationships between serum carbamazepine and its metabolites in epileptic children.
The influence of polytherapy on the relationships between the age, weight, carbamazepine (CBZ) dose, total clearance, and intrinsic clearance, with concentrations, concentration ratios, and level/dose ratios of CBZ, carbamazepine-10,11-epoxide (CBZ-E) and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) are investigated. Three groups of patients with CBZ monotherapy, or receiving CBZ polytherapy by taking CBZ and valproic acid (VPA) or CBZ plus other antiepileptic drugs (AEDs) were studied. The significant correlations between serum CBZ concentrations and CBZ dose in patients taking CBZ alone were no longer significant in patients with polytherapy, and the positive associations between serum CBZ-E concentrations and CBZ dose were lost in patients with CBZ + VPA. Only the concentrations of CBZ-H had significant correlations with CBZ dose in all three groups of patients. Results from this relationship study indicate a heteroinduction effect of other AEDs on CBZ metabolism, and a relatively weak influence on CBZ-E elimination. Data also suggest that there is a block in the biotransformation from CBZ-E to CBZ-H in patients taking CBZ + VPA, presumably caused by the inhibition effect of VPA on epoxide hydrolase. Therapeutic drug monitoring of CBZ will benefit from the knowledge obtained from the relationship study.
Department of Research, Texas Scottish Rite Hospital for Children, University of Texas Southwestern Medical Center, Dallas 75219.
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Delgado
D000375:Aging / Q000378:metabolism; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D013056:Spectrophotometry, Ultraviolet; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use
D000927:Anticonvulsants; D002220:Carbamazepine; C004822:10,11-dihydro-10,11-dihydroxy-5H-dibenzazepine-5-carboxamide; D014635:Valproic Acid; C012227:carbamazepine epoxide