The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

Autor:	Cheruvu N; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., van Duijn E; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Spigt PA; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Barbu IM; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Toussi SS; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Schildknegt K; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Jones RM; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.)., Obach RS; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut (R.S.O., K.S.); Pfizer Worldwide Research, Development and Medical, La Jolla, California (R.M.J.); Pfizer Worldwide Research, Development and Medical, Collegeville, Pennsylvania (N.C.); Pfizer Worldwide Research, Development and Medical, Pearl River, New York (S.S.T.); and The Netherlands Organization for Applied Scientific Research (T.N.O.), Zeist, Netherlands (E.v.D., P.A.S., I.M.B.) r.scott.obach@pfizer.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Oct; Vol. 51 (10), pp. 1419-1427. Date of Electronic Publication: 2023 Jul 10.
DOI:	10.1124/dmd.123.001416
Abstrakt:	The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19. On administration of [ 14 C]lufotrelvir, only 63% of the dose was obtained in excreta over 10 days and total drug-related material demonstrated a prolonged terminal phase half-life in plasma. A considerable portion of the labeled material was unextractable from fecal homogenate and plasma. The position of the carbon-14 atom in the labeled material was at a leucine carbonyl, and pronase digestion of the pellet derived from extraction of the fecal homogenate showed that [ 14 C]leucine was released. SIGNIFICANCE STATEMENT: Lufotrelvir is an experimental phosphate prodrug intravenous therapy investigated for the potential treatment of COVID-19 in a hospital setting. The overall metabolism of lufotrelvir was determined in human healthy volunteers and clinical trial participants with COVID-19. Conversion of the phosphate prodrug to the active drug PF-00835231 was complete and the subsequent metabolic clearance of the active drug was largely via amide bond hydrolysis. Substantial drug-related material was not recovered due to loss of the carbon-14 label to endogenous metabolism. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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