Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

Tolvaptan is a vasopressin

Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19)

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15–50 μM), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil, MK-571, or 10 μM elacridar. Coincubation of tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing tolvaptan concentrations (0.15–50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μM tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites

Supplemental Material, DS1_IJT_10.1177_1091581818760746 - Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease

<p>Supplemental Material, DS1_IJT_10.1177_1091581818760746 for Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease by William J. Brock, James J. Beaudoin, Jason R. Slizgi, Mingming Su, Wei Jia, Sharin E. Roth, and Kim L. R. Brouwer in International Journal of Toxicology</p

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

Tolvaptan is a selective V(2)-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15–50 μM), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil, MK-571, or 10 μM elacridar. Coincubation of tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing tolvaptan concentrations (0.15–50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μM tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites

Intrinsic relative activities of κ opioid agonists in activating Gα proteins and internalizing receptor: Differences between human and mouse receptors

Several investigators recently identified biased opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [(35)S]GTPγS binding and KOP receptor internalization as measures of activation of G protein and β-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation (RA(i−G)) and receptor internalization (RA(i−I)) and the degree of functional selectivity between the two [Log RA(i−G) − Log RA(i−I), RA(i−G)/RA(i−I) and bias factor]. The parameter, RA(i), represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1–17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12-epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed