title: Timing and Duration of Drug Exposure Affects Outcomes of a Drug-Nutrient Interaction During Ontogeny.
abstract: Significant drug-nutrient interactions are possible when drugs and nutrients share the same absorption and disposition mechanisms. During postnatal development, the outcomes of drug-nutrient interactions may change with postnatal age since these processes undergo ontogenesis through the postnatal period. Our study investigated the dependence of a significant drug-nutrient interaction (cefepime-carnitine) on the timing and duration of drug exposure relative to postnatal age. Rat pups were administered cefepime (5 mg/kg) twice daily subcutaneously according to different dosing schedules (postnatal day 1-4, 1-8, 8-11, 8-20, or 1-20). Cefepime significantly reduced serum and heart L-carnitine levels in postnatal day 1-4, 1-8 and 8-11 groups and caused severe degenerative changes in ventricular myocardium in these groups. Cefepime also altered the ontogeny of several key L-carnitine homeostasis pathways. The qualitative and quantitative changes in levels of hepatic γ-butyrobetaine hydroxylase mRNA and activity, hepatic trimethyllysine hydroxlase mRNA, intestinal organic cation/carnitine transporter (Octn) mRNA, and renal Octn2 mRNA depended on when during postnatal development the cefepime exposure occurred and duration of exposure. Despite lower levels of heart L-carnitine in earlier postnatal groups, levels of carnitine palmitoyltransferase mRNA and activity, heart Octn2 mRNA and ATP levels in all treatment groups remained unchanged with cefepime exposure. However, changes in other high energy phosphate substrates were noted and reductions in the phosphocreatine/ATP ratio were found in rat pups with normal serum L-carnitine levels. In summary, our data suggest a significant drug-nutrient transport interaction in developing neonates, the nature of which depends on the timing and duration of exposure relative to postnatal age.
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, S7N5C9, Canada.
authors.forename: Binbing
authors.initials: B
authors.lastname: Ling
authors.affiliation: Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK, S7N 5B3, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Aziz
authors.affiliation: Department of Veterinary Pathology, Prairie Diagnostic Services, 52 Campus Drive, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Wojnarowicz
authors.affiliation: Department of Animal and Poultry Science, University of Saskatchewan, 51 Campus Drive Saskatoon, SK, S7N 5A8, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Olkowski
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, S7N5C9, Canada. jane.alcorn@usask.ca.
authors.forename: Jane
authors.initials: J
authors.lastname: Alcorn
keywords: L-carnitine; cefepime; drug-nutrient interaction; ontogeny; windows of susceptibility