Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17β-HSD1 for breast cancer and endometriosis treatments

Maltais R, René Maltais, Trottier A, Alexandre Trottier, Roy J, Jenny Roy, Diana Ayán, Diana Ayan, Nicolas Bertrand, Poirier D, Donald Poirier
The Journal of steroid biochemistry and molecular biology · 2017 · vol. 178 , pp. 167–176 · doi:10.1016/j.jsbmb.2017.12.007 · PMID:29248731 · W2771931566
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This study characterized the pharmacokinetic profile of PBRM, a novel selective covalent inhibitor of 17β-HSD1, in rodents as a potential therapeutic for breast cancer and endometriosis.

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Abstract

The development of a covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a promising approach for the treatment of hormone-dependent breast cancer and endometriosis. After reporting the steroid derivative PBRM as a first potent covalent inhibitor of 17β-HSD1 without estrogenic activity, we are now interested in studying its pharmaceutical behavior. The metabolism study in a human liver microsomal preparation showed a gradual transformation of PBRM into PBRM-O, an oxidized ketonic form of PBRM at position C17. Interestingly, PBRM-O also inhibits 17β-HSD1 and is not estrogenic in estrogen-sensitive T-47D cells. However, when PBRM was injected subcutaneously (sc) in mice, a very small proportion of PBRM-O was measured in a 24 h-time course experiment. A pharmacokinetic study in mice revealed suitable values for half-life (T1/2 = 3.4 h), clearance (CL = 2088 mL/h kg), distribution volume (Vz = 10.3 L/kg) and absolute bioavailability (F = 65%) when PBRM was injected sc at 14.7 mg/kg. A good F value of 33% was also obtained when PBRM was given orally. A tritiated version of PBRM, 3H-PBRM, was synthesized and used for an in vivo biodistribution study that showed its gradual accumulation in various mouse tissues (peak at 6 h) followed by elimination until complete disappearance after 72 h. Elimination was found to occur in feces (93%) and urine (7%) as revealed by a mass balance experiment. PBRM was also evaluated for its toxicity in mice and it was found to be very well tolerated after weekly sc administration (30-405 mg/kg for 8 weeks) or by po administration (300-900 mg/kg for 4 weeks). Overall, these experiments represent important steps in the preclinical characterization of the pharmaceutical behavior of PBRM, as well as for its translation to clinical trials.

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Condition tags

endometriosis

MeSH descriptors

Benzamides Breast Neoplasms Endometriosis Enzyme Inhibitors Estradiol Dehydrogenases Animals Animals Apoptosis Apoptosis Benzamides Benzamides Benzamides Benzamides Breast Neoplasms Breast Neoplasms Breast Neoplasms Breast Neoplasms Cell Proliferation Cell Proliferation Endometriosis

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