Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models.

Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, and safety profile. In vitro pharmacologic activities and the mechanisms of action of R-DXd were assessed in serous-type ovarian cancer and renal cell carcinoma cell lines.

Estimation of fraction of drug metabolism by a single UDP-glucuronosyl transferase enzyme using relative expression factor.

The estimation of the contributions of UDP-glucuronosyl transferase (UGT) isoforms to the overall metabolism still suffers from technical difficulties due to limited information on enzyme levels in recombinant systems and specific inhibitors, unlike the case for cytochrome P450s (CYPs). The protein expression levels of UGT in both recombinant system microsomes (RM) and human liver microsomes (HLM) were quantified using liquid chromatography-tandem mass spectrometry, and the relative expression factor (REF) value of HLM to recombinant microsomes was estimated to evaluate the fractions of drug metabolism by a single UGT enzyme (fmUGT) of UGT substrates. The REF values of UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 were 0.

Species differences between rats and primates (humans and monkeys) in complex cleavage pathways of DS-8500a characterized by C-ADME studies in humans and monkeys after administration of two radiolabeled compounds and in vitro studies.

Our previous study in rats demonstrated that the metabolic pathways of DS-8500a, a novel GPR119 agonist, include cleavage pathways: reductive cleavage of the oxadiazole ring in the liver and hydrolysis of the amide side chain. In the present study, in vivo metabolic profiling in humans and monkeys after the oral administration of two C-labeled compounds was performed to investigate species differences of the cleavage pathways. In monkeys, the oxadiazole ring-cleaved metabolites were mainly detected in feces, but not observed in bile, unlike in rats, suggesting that the reductive ring-opening metabolism occurs in the gastrointestinal tract.

Pharmacokinetics and metabolism of mirogabalin, a novel αδ ligand, in rats and monkeys.

The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [C]mirogabalin.

Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models.

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin.

Loxoprofen (LX) is a prodrug-type non-steroidal anti-inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans-alcohol form of LX (trans-OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans-OH form in human in vitro skin and to identify the predominant enzyme for its generation.

CYP2D6-Mediated metabolism of a novel acyl coenzyme A:cholesterol acyltransferase inhibitor, pactimibe, and its unique plasma metabolite, R-125528.

Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor. We conducted metabolic studies of pactimibe and its plasma metabolite, R-125528. Pactimibe had multiple metabolic pathways including indolin oxidation to form R-125528, omega-1 oxidation, N-dealkylation, and glucuronidation.