Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers

Aims In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated. Methods Using repeated oral microdoses (30 μg) of the C...

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Published in:British journal of clinical pharmacology 2023-08, Vol.89 (8), p.2458-2464
Main Authors: Breithaupt, Mareile H., Krohmer, Evelyn, Taylor, Lenka, Körner, Eva, Hoppe‐Tichy, Torsten, Burhenne, Juergen, Foerster, Kathrin I., Dachtler, Markus, Huber, Gerald, Venkatesh, Rakesh, Eggenreich, Karin, Czock, David, Mikus, Gerd, Blank, Antje, Haefeli, Walter E.
Format: Article
Language:English
Subjects:
Administration, Oral
Area Under Curve
Cytochrome P-450 CYP3A - metabolism
cytochrome P‐450 CYP3A
dipyrone
Dipyrone - pharmacology
drug interaction
Drug Interactions
enzyme induction
Healthy Volunteers
Humans
Kinetics
midazolam
Midazolam - pharmacokinetics
time factors
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Summary:Aims In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated. Methods Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration–time curve from 2–4 h: AUC2–4 and estimated partial metabolic clearance: eClmet) before, at steady‐state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days. Results Significant changes in pharmacokinetic parameters were detected already 3 days after start of metamizole treatment. At the steady‐state of enzyme induction, the geometric mean ratio of midazolam AUC2–4 was substantially reduced to 0.18 (90% confidence interval: 0.14–0.24) with a corresponding 5.43‐fold (4.15–7.10) increase of eClmet. After discontinuation of metamizole, the changes slowly recovered, but were still significant at the end of the observation period on the fifth day after discontinuation of metamizole therapy (AUC2–4 reduced to 0.50 [0.41–0.63] and eClmet 1.99‐fold increased [1.60–2.47, P 
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.15720