Abstract
The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver cytochrome P450. Both drugs displayed a type II spectra. The K(s) values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C 3-hydroxylatio and N 1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 x 10 -7 and 2.95 x 10 -7 M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C 3-hydroxylation were 1.44 x 10 -6 and 1.00 x 10 -6 M, respectively, and those for N 1-dealkylation 6.66 x 10 -7 and 5.95 x 10 -7 M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vitro after single oral doses (15 and/or 60 mg kg -1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.
| Original language | English |
|---|---|
| Pages (from-to) | 17-21 |
| Number of pages | 5 |
| Journal | Journal of Pharmacy and Pharmacology |
| Volume | 40 |
| Issue number | 1 |
| Publication status | Published - 1988 |
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ASJC Scopus subject areas
- Pharmaceutical Science
- Pharmacology
Cite this
Interaction of the anticonvulsants, denzimol and nafimidone, with liver cytochrome P450 in the rat. / Salmona, M.; Conti, I.; Testa, R.; Fracasso, C.; Caccia, S.
In: Journal of Pharmacy and Pharmacology, Vol. 40, No. 1, 1988, p. 17-21.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interaction of the anticonvulsants, denzimol and nafimidone, with liver cytochrome P450 in the rat
AU - Salmona, M.
AU - Conti, I.
AU - Testa, R.
AU - Fracasso, C.
AU - Caccia, S.
PY - 1988
Y1 - 1988
N2 - The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver cytochrome P450. Both drugs displayed a type II spectra. The K(s) values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C 3-hydroxylatio and N 1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 x 10 -7 and 2.95 x 10 -7 M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C 3-hydroxylation were 1.44 x 10 -6 and 1.00 x 10 -6 M, respectively, and those for N 1-dealkylation 6.66 x 10 -7 and 5.95 x 10 -7 M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vitro after single oral doses (15 and/or 60 mg kg -1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.
AB - The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver cytochrome P450. Both drugs displayed a type II spectra. The K(s) values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C 3-hydroxylatio and N 1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 x 10 -7 and 2.95 x 10 -7 M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C 3-hydroxylation were 1.44 x 10 -6 and 1.00 x 10 -6 M, respectively, and those for N 1-dealkylation 6.66 x 10 -7 and 5.95 x 10 -7 M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vitro after single oral doses (15 and/or 60 mg kg -1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.
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M3 - Article
C2 - 2896768
AN - SCOPUS:0023832271
VL - 40
SP - 17
EP - 21
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
SN - 0022-3573
IS - 1
ER -