Objective: The pharmacokinetics, metabolism and excretion of MEP and DEP were studied in the juvenile dog to compare the MEP exposure after intravenous or oral administration of 14C-MEP or 14C-DEP in juvenile beagle dogs.
Methods: Four male juvenile beagle dogs (12-weeks old at the beginning of treatment) were treated with a single oral or bolus intravenous dose of either 14C-MEP or 14C-DEP (ca.1200 μg or 164 μg/kg; 89 μCi/dog). Following dose administration, blood samples were collected up to 24 h post-dose, and urine and faeces were quantitatively collected for up to 72 h post-dose. Plasma, urine, and faeces were analysed for total radioactivity (TR). Urinary and plasma metabolites were profiled by HPLC equipped with a radioactivity detector and the attempt to identify major urine metabolites was performed by LC-MS. Pharmacokinetic parameters of MEP and DEP were determined. During the initial phases of the study, dogs were (for companionship) housed in pairs and a crossover dosing regime was used to eliminate bias caused by ageing.
Results: The absorption, metabolism and excretion of 14C-MEP were near identical to that of 14C-DEP. 14C-DEP was rapidly and near completely metabolized to 14C-MEP following either intravenous or oral administration. The peak plasma levels of TR were reached within 30 minutes after oral administration with either 14C-MEP or 14C-DEP, the elimination half-life of MEP was estimated to be 1 h. TR was mainly excreted in urine (90 - 96% of the dose) with faecal excretion accounting for only a minor fraction of the total excreted radioactivity (2 – 3% of the dose). In plasma, MEP accounted for the majority of TR, in addition, three minor metabolites (M1, M2 and M3) were detected. In urine, MEP was the major component, and the three minor plasma metabolites were also observed with M3 accounting for approximately 12% of the dose. The metabolites are neither phthalic acid, nor glucuronide/sulfate conjugates.
Conclusions: The present data demonstrated that DEP was rapidly and near completely metabolized to MEP after intravenous or oral administration. The absorption, metabolism and excretion of 14C-MEP and 14C-DEP in juvenile beagle dogs were indistinguishable, consequently the pharmacokinetics of MEP and DEP was near identical. The near identical metabolism and pharmacokinetics of MEP and DEP in juvenile dogs provided the scientific rationale of possible use of DEP data for the risk assessment of MEP exposure in humans, especially in pediatric population.