L'Aurelle A Johnson1, Natalia Tretyakova, Pamala A Jacobson. 1. University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, 308 Harvard Street SE, 7-115C WDH, Minneapolis, MN 55443, USA. joh02745@umn.edu
Abstract
BACKGROUND: Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA-DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NOR-G crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks. PATIENTS AND METHODS: Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured. RESULTS: Overweight/obese patients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obese patients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC(0-∞)) =529.24 vs. 867.99 μcg/ml*h respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC(0-∞)=142.8 vs. 147.0 adducts/10(6) nucleotides*h, respectively, p=0.59. CONCLUSION: Overweight/obese patients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.
BACKGROUND:Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA-DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NOR-G crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks. PATIENTS AND METHODS: Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured. RESULTS: Overweight/obesepatients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obesepatients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC(0-∞)) =529.24 vs. 867.99 μcg/ml*h respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC(0-∞)=142.8 vs. 147.0 adducts/10(6) nucleotides*h, respectively, p=0.59. CONCLUSION: Overweight/obesepatients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.
Authors: Veronika Bachanova; John Rogosheske; Ryan Shanley; Linda J Burns; Sara M Smith; Daniel J Weisdorf; Claudio G Brunstein Journal: Biol Blood Marrow Transplant Date: 2015-10-21 Impact factor: 5.742