ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

• Published in: Brazilian journal of medical and biological research 2016-01, Vol.49 (12), p.e5542-e5542
• Main Authors: Noël, F, Nascimento-Viana, J B, Romeiro, L A S, Silva, R O, Lemes, L F N, Oliveira, A S, Giorno, T B S, Fernandes, P D, Silva, C L M
• Format: Article
• Language: English
• Subjects: ADME; Animals; Benign prostatic hyperplasia; BIOLOGY; Biomedical Sciences; Care and treatment; CYP; Drug Evaluation, Preclinical; Drug Stability; Elderly; Female; Health aspects; Humans; Male; MEDICINE, RESEARCH & EXPERIMENTAL; Mice; Permeability; Physiological aspects; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Preclinical development; Prostatic hyperplasia; Prostatic Hyperplasia - drug therapy; Quality of life; Rats; Safety; Time Factors
• ISSN: 0100-879X; 1414-431X; 1414-431X
• DOI: 10.1590/1414-431X20165542

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.