Nefazodone inhibits methylprednisolone disposition and enhances its adrenal-suppressant effect.
Nefazodone is a potent and selective inhibitor of cytochrome P450 3A4 (CYP3A4), an enzyme pathway responsible for the biotransformation of a number of steroid compounds. The potential therefore exists that nefazodone inhibits the disposition of methylprednisolone. In this open label, repeated measures study, the effect of 9 days of nefazodone administration on the pharmacokinetic disposition of a single 0.6 mg/kg intravenous dose of methylprednisolone was assessed. Additionally the effect of concomitant nefazodone use on duration of cortisol suppression after methylprednisolone administration was assessed. Eight healthy volunteers completed the study. Following nefazodone administration, the mean (+/-SD) area under the methylprednisolone concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02). The duration of cortisol suppression after methylprednisolone administration was longer (> or =32 vs. 23.3 +/- 3.43 hours) during nefazodone administration.
Kotlyar
Michael
M
School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. kotly001@umn.edu
Brewer
Edwin R
ER
Golding
Michael
M
Carson
Stanley W
SW
D000302:Adrenal Cortex / Q000187:drug effects*; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000493:pharmacokinetics*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics*; D010879:Piperazines; D012016:Reference Values; D014230:Triazoles / Q000494:pharmacology*
D018687:Antidepressive Agents, Second-Generation; D065607:Cytochrome P-450 Enzyme Inhibitors; D005938:Glucocorticoids; D010879:Piperazines; D014230:Triazoles; C051752:nefazodone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone; D008775:Methylprednisolone