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Changes in Alprazolam Metabolism by CYP3A43 Mutants

ORCID
0000-0002-0776-9563
Affiliation
School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China
Zhao, Jie;
ORCID
0000-0001-8834-3881
Affiliation
Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universitaet Berlin, Koenigin-Luise-Strasse 2+4, 14195 Berlin, Germany
Liu, Sijie;
ORCID
0000-0002-5682-1815
Affiliation
Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universitaet Berlin, Koenigin-Luise-Strasse 2+4, 14195 Berlin, Germany
Wolf, Clemens Alexander;
ORCID
0000-0002-5344-0048
Affiliation
Pharmaceutical and Medicinal Chemistry (Computer-Aided Drug Design), Institute of Pharmacy, Freie Universitaet Berlin, Koenigin-Luise-Strasse 2+4, 14195 Berlin, Germany
Wolber, Gerhard;
ORCID
0000-0001-7407-8300
Affiliation
Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analysis), Institute of Pharmacy, Freie Universitaet Berlin, Koenigin-Luise-Strasse 2+4, 14195 Berlin, Germany
Parr, Maria Kristina;
ORCID
0000-0002-9515-6248
Affiliation
School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China
Bureik, Matthias

Alprazolam is a triazolobenzodiazepine which is most commonly used in the short-term management of anxiety disorders, often in combination with antipsychotics. The four human members of the CYP3A subfamily are mainly responsible for its metabolism, which yields the main metabolites 4-hydroxyalprazolam and α-hydroxyalprazolam. We performed a comparison of alprazolam metabolism by all four CYP3A enzymes upon recombinant expression in the fission yeast Schizosaccharomyces pombe . CYP3A4 and CYP3A5 show the highest 4-hydroxyalprazolam production rates, while CYP3A5 alone is the major producer of α-hydroxyalprazolam. For both metabolites, CYP3A7 and CYP3A43 show lower activities. Computational simulations rationalize the difference in preferred oxidation sites observed between the exemplary enzymes CYP3A5 and CYP3A43. Investigations of the alprazolam metabolites formed by three previously described CYP3A43 mutants (L293P, T409R, and P340A) unexpectedly revealed that they produce 4-hydroxy-, but not α-hydroxyalprazolam. Instead, they all also make a different metabolite, which is 5-N-O alprazolam. With respect to 4-hydroxyalprazolam, the mutants showed fourfold (T409R) to sixfold (L293P and P340A) higher production rates compared to the wild-type (CYP3A43.1). In the case of 5-N-O alprazolam, the production rates were similar for the three mutants, while no formation of this metabolite was found in the wild-type incubation.

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