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Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics.
Ramirez, Dominique A; Collins, Keagan P; Aradi, Allister E; Conger, Katherine A; Gustafson, Daniel L.
Afiliación
  • Ramirez DA; Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado mando.ramirez@colostate.edu.
  • Collins KP; Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado.
  • Aradi AE; Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado.
  • Conger KA; Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado.
  • Gustafson DL; Department of Clinical Sciences (D.A.R., A.E.A., D.L.G.) and School of Biomedical Engineering (K.P.C., K.A.C., D.L.G.), Colorado State University, Fort Collins, and University of Colorado Cancer Center, Aurora (D.L.G.), Colorado.
Drug Metab Dispos ; 47(3): 257-268, 2019 03.
Article en En | MEDLINE | ID: mdl-30567881
Cyclophosphamide (CP), a prodrug that is enzymatically converted to the cytotoxic 4-hydroxycyclophosphamide (4OHCP) by hepatic enzymes, is commonly used in both human and veterinary medicine to treat cancers and modulate the immune system. We investigated the metabolism of CP in humans, dogs, cats, and mice using liver microsomes; apparent K M, V max, and intrinsic clearance (V max/K M) parameters were estimated. The interspecies and intraspecies variations in kinetics were vast. Dog microsomes were, on average, 55-fold more efficient than human microsomes, 2.8-fold more efficient than cat microsomes, and 1.2-fold more efficient than mouse microsomes at catalyzing CP bioactivation. These differences translated to cell-based systems. Breast cancer cells exposed to 4OHCP via CP bioactivation by microsomes resulted in a stratification of cytotoxicity that was dependent on the species of microsomes measured by IC50: dog (31.65 µM), mouse (44.95 µM), cat (272.6 µM), and human (1857 µM). The contributions of cytochrome P450s, specifically, CYP2B, CYP2C, and CYP3A, to CP bioactivation were examined: CYP3A inhibition resulted in no change in 4OHCP formation; CYP2B inhibition slightly reduced 4OHCP in humans, cats, and mice; and CYP2C inhibition drastically reduced 4OHCP formation in each species. Semiphysiologic modeling of CP metabolism using scaled metabolic parameters resulted in simulated data that closely matched published pharmacokinetic profiles, determined by noncompartmental analysis. The results highlight differential CP metabolism delineated by species and demonstrate the importance of metabolism on CP clearance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Antineoplásicos Alquilantes / Ciclofosfamida / Inmunosupresores / Modelos Biológicos Límite: Animals / Female / Humans / Male Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Antineoplásicos Alquilantes / Ciclofosfamida / Inmunosupresores / Modelos Biológicos Límite: Animals / Female / Humans / Male Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos