Timing and Duration of Drug Exposure Affects Outcomes of a Drug-Nutrient Interaction During Ontogeny.

Binbing Ling,Jane Alcorn,Caroline Aziz,Chris Wojnarowicz,Andrew Olkowski

doi:10.3390/pharmaceutics2040321

Binbing Ling, Jane Alcorn + Show 3 more

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https://doi.org/10.3390/pharmaceutics2040321

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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.

Highlights

Postnatal life represents a period of significant susceptibility to nutritional alterations that may affect maturing biochemical and physiological processes with long-term consequences on individual health [1,2]
This study demonstrated that cefepime administration altered L-carnitine homeostasis pathways in neonatal rats
Our results suggest that neonates have the capacity to adjust their renal L-carnitine reabsorption by changing organic cation/carnitine transporter 2 (Octn2) expression levels, the principle transporter involved in the active reabsorption of L-carnitine from the urinary filtrate [43]

Summary

Introduction

Postnatal life represents a period of significant susceptibility to nutritional alterations that may affect maturing biochemical and physiological processes with long-term consequences on individual health [1,2]. Despite a general acknowledgement that drug use may impact normal development of the physiological system [8], limited research has examined the consequences of pharmacological interventions on the developing neonate, when drugs influence nutrient availability in the body [9] Both nutrient homeostasis pathways and processes governing drug pharmacokinetics in neonates may undergo significant ontogenesis in the postnatal period [10]. When a drug and nutrient share the same absorption and/or disposition mechanism, a significant drug-nutrient interaction during postnatal development is possible and this interaction could affect the ontogeny of these pathways Such effects may be transient with the normal genetic programming restored upon removal of the drug exposure, or permanent changes may occur when drug exposure occurs during a critical window of susceptibility [11,12]. Fewer studies have evaluated the influence of drugs on nutrient homeostasis [9,18]

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