Mass Balance and Absorption, Distribution, Metabolism, and Excretion Properties of Balcinrenone following Oral Administration in Combination with Intravenous Microtracer in Healthy Subjects.

Autor:	Lindmark B; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Li XQ; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Bhattacharya C; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Housler G; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Heijer M; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Bragg RA; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Gränfors M; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Pelay-Gimeno M; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Vaes WHJ; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Menakuru S; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Pizzato PE; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Ericsson H; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.)., Johansson S; Drug Metabolism and Pharmacokinetics, Early Research and Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (B.L., X.-Q.L.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (G.H.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden(M.H., H.E., S.J.); Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); Early Product Development and Manufacture, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (M.G.); Quotient Sciences, Nottingham, United Kingdom (S.M.); Early Clinical Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.E.P.); and TNO, Leiden, Netherlands (M.P.-G., W.H.J.V.) susanne.a.johansson@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Aug; Vol. 51 (8), pp. 995-1004. Date of Electronic Publication: 2023 Jul 05.
DOI:	10.1124/dmd.122.001240
Abstrakt:	An absorption, distribution, metabolism, and excretion study was performed to determine the basic pharmacokinetic parameters, mass balance, and metabolite profiles of balcinrenone, a mineralocorticoid receptor modulator, in humans. This open-label, single-center, nonrandomized study had a two-period design. In period 1, eight healthy male subjects were dosed with a microtracer intravenous infusion of [ 14 C]balcinrenone shortly after receiving an oral dose of unlabeled balcinrenone in a capsule. Following a 7-day washout, the same group of subjects subsequently received an oral dose of [ 14 C]balcinrenone as a suspension in period 2. Clearance and absolute bioavailability of balcinrenone were determined to be 14.2 l/h and 52%, respectively. Renal clearance was determined to be 5.4 l/h (>fu • glomerular filtration rate), indicating elimination via active tubular secretion, which was potentially mediated by P-glycoprotein 1 and/or organic anion transporter 3, according to in vitro transporter data. In total, 94.1% of the oral dose was recovered: 45.2% in the urine and 48.9% in the feces. Balcinrenone was primarily metabolized via oxidation, and in vitro data suggest that cytochrome P450 3A4 was the main enzyme responsible. Intact [ 14 C]balcinrenone accounted for 55% of drug-related material in the plasma; four metabolites were identified, each representing <6% of the total plasma radioactivity. In conclusion, this two-period study has determined the basic pharmacokinetic parameters of balcinrenone in humans, including absolute bioavailability and disposition. No metabolites warranted further evaluation on account of their low representation, and any contribution to the pharmacodynamic response or potential drug-drug interactions was deemed negligible. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the pharmacokinetics, disposition, and metabolism of balcinrenone following oral and microtracer intravenous administration in humans. In vitro phenotyping and transporter data granted mechanistic insights into the absorption, distribution, metabolism, and excretion properties of balcinrenone. This knowledge will guide future nonclinical and clinical studies evaluating drug-drug interactions, organ dysfunction, and safety of metabolites. (Copyright © 2023 by The Author(s).)
Databáze:	MEDLINE
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