Abiraterone D4A metabolite, the product of 3β-hydroxysteroid dehydrogenase activity toward abiraterone, may serve as a potential antitumor agent for the treatment of prostate cancer. The main adverse effect of abiraterone is the disruption of corticosteroid biosynthesis, and the more pharmacologically active abiraterone D4A metabolite may have the same issues. We therefore estimated the inhibiting impact of the abiraterone D4A metabolite on one of the key corticosteroidogenic enzymes - human steroid 21-monooxygenase (CYP21A2). Molecular docking of D4A into the active site of CYP21A2 has been predicted to be similar to abiraterone binding with the enzyme. Abiraterone D4A metabolite, similar to abiraterone, induces type II spectral changes of CYP21A2. The spectral dissociation constant for the abiraterone D4A metabolite-CYP21A2 complex was calculated as 3.4 ± 0.5 μM. Abiraterone D4A metabolite demonstrates competitive/mixed type CYP21A2 inhibition with an inhibitory constant of 1.8 ± 0.8 μM, as obtained by Dixon plot. These results make it possible to predict the adverse effects of the new perspective candidate compound for antitumor therapy.
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Article Synopsis
- Researchers developed and validated a new, quick, and accurate LC-MS/MS method for measuring abiraterone and its metabolites in human plasma, employing methods like protein precipitation and gradient elution.
- The study showed good accuracy and precision in the quantification of all analytes, with favorable stability results indicating that the samples could be kept under various conditions without significant degradation.
- The method was successfully used in a pharmacokinetic study involving healthy Chinese volunteers to analyze how the drug and its metabolites behave in the body after a single dose of abiraterone acetate.
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