Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol
| Autor: | A. Craig Eddy, Jacques A. Tor, Bradley M. Kerr, C. Viteri, Juan M. Martinez-Lage, René H. Levy |
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| Rok vydání: | 1991 |
| Předmět: |
Adult
Male medicine.medical_treatment Pharmacology Pharmacokinetics Cytochrome P-450 Enzyme System Blood plasma medicine Stiripentol Humans Drug Interactions Biotransformation Aged Epilepsy biology Chemistry Cytochrome P450 Dioxolanes Carbamazepine Drug interaction Anticonvulsant Neurology Microsome biology.protein Microsomes Liver Female Neurology (clinical) medicine.drug |
| Zdroj: | Epilepsia. 32(2) |
| ISSN: | 0013-9580 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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