Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo.
OBJECTIVE
To study the effects of methylprednisolone on the pharmacokinetics and pharmacodynamics of triazolam.


METHODS
In this three-phase cross-over study, ten healthy subjects received 0.25 mg oral triazolam on three occasions: on day 1 (no pretreatment, control), on day 8 (1 h after a single dose of 32 mg oral methylprednisolone) and on day 18 (after further treatment with 8 mg oral methylprednisolone daily for 9 days). The plasma concentrations of triazolam were determined up to 10 h, and its effects were measured using four psychomotor tests up to 6 h.


RESULTS
The single dose of methylprednisolone showed no significant effects on the pharmacokinetics of triazolam. However, the Digit Symbol Substitution Test result was better (P < 0.05) during the single-dose methylprednisolone phase than during the control phase, the other three tests showing no differences between the phases. The multiple-dose treatment with methylprednisolone reduced the mean peak plasma concentration (Cmax) of triazolam by 30% (P < 0.05) but had no significant effects on the time to Cmax (tmax), elimination half-life (t 1/2), area under the plasma concentration-time curve from 0 h to 10 h (AUC(0-10 h)) and AUC(0-infinity) and did not alter the effects of triazolam.


CONCLUSIONS
A single, relatively high dose of methylprednisolone (32 mg) did not affect cytochrome P450 (CYP)3A4 activity, and treatment with 8 mg methylprednisolone daily for 9 days did not result in clinically significant induction of CYP3A4.
Villikka
K
K
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital. Finland
Varis
T
T
Backman
J T
JT
Neuvonen
P J
PJ
Kivistö
K T
KT
D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics* / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D014229:Triazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D005938:Glucocorticoids; D014229:Triazolam; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008775:Methylprednisolone