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Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses
Author(s) -
Hohmann Nicolas,
Blank Antje,
Burhenne Jürgen,
Suzuki Yosuke,
Mikus Gerd,
Haefeli Walter E.
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14040
Subject(s) - chlorzoxazone , pharmacology , midazolam , pharmacokinetics , microdose , chemistry , cyp3a , drug interaction , medicine , cyp2e1 , cytochrome p450 , biochemistry , sedation , enzyme
Aims Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250–750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem. Method We enrolled 12 healthy volunteers in a trial investigating the dose–exposure relationship of single ascending chlorzoxazone oral doses over a 10,000‐fold range (0.05–500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg). Results Chlorzoxazone area under the concentration–time curve was dose‐linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration–time curve increased 2‐fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses. Conclusion The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.