Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol.
The inhibitory effect of stiripentol (STP) on disposition of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZE) was quantitated to establish CBZ dosage reduction guidelines for future clinical add-on efficacy trials of STP. In seven epileptic patients, STP (1,500-3,000 mg/day for 2 weeks) inhibited CBZ clearance by 50 +/- 16% (p = 0.001) and reduced the CBZE/CBZ plasma ratio by 45 +/- 14% (p = 0.0005). The inhibitory effect was gradually manifested over a period of 7-10 days after initiation of STP therapy. In contrast to inhibition of CBZE formation, STP had no effect (p greater than 0.05) on elimination clearance or half-life (t1/2) of CBZE in six healthy volunteers. STP most likely exerts inhibitory effects through inhibition of cytochrome P-450. This hypothesis was confirmed in the present study by the finding that a therapeutic concentration of STP (7 micrograms/mL) inhibited 10,11-epoxidation of CBZ in human liver microsomes by 40-50%. On the basis of results from this study, we propose that (a) CBZ dosage should be reduced in steps over a period of 7-10 days after initiation of STP, and (b) a CBZ dosage of 4.3 to 8.7 mg/kg/day will maintain therapeutic CBZ plasma levels of 5-10 micrograms/mL.
Kerr
B M
BM
Department of Pharmaceutics, University of Washington, Seattle 98195.
Martinez-Lage
J M
JM
Viteri
C
C
Tor
J
J
Eddy
A C
AC
Levy
R H
RH
D000328:Adult; D000368:Aged; D001711:Biotransformation / Q000187:drug effects; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004148:Dioxolanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism
D004148:Dioxolanes; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; C012227:carbamazepine epoxide; C021092:stiripentol