In Vivo Metabolism of Ibuprofen in Growing Conventional Pigs: A Pharmacokinetic Approach.

Joske Millecam,Mathias Devreese,Siska Croubels,Siegrid De Baere

doi:10.3389/fphar.2019.00712

Abstract

The juvenile conventional pig has been suggested as a preclinical animal model to evaluate pharmacokinetic (PK), pharmacodynamic (PD), and safety parameters in children. However, a lot of developmental changes in pig physiology still need to be unraveled. While the in vitro ontogeny of pig biotransformation enzymes is getting more attention in literature, the in vivo developmental changes have not yet been investigated. Therefore, the aim of the current study was to evaluate the biotransformation of ibuprofen (IBU) in conventional pigs aged 1 week, 4 weeks, 8 weeks, and 6–7 months after a single intravenous and oral administration of 5 mg/kg body weight (BW) of IBU, using a PK approach in a crossover design for each age group. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine 2-hydroxyibuprofen (2OH-IBU), carboxyibuprofen (COOH-IBU), and ibuprofen glucuronide (IBU-GlcA) in pig plasma. All three metabolites could be quantified in plasma and the following PK parameters were determined: C max, T max, AUC0→6h, area under plasma concentration–time curve (AUC) ratio between parent drug and metabolite, and the absolute oral bioavailability of the parent drug IBU. The plasma concentrations of the metabolites were always lower than those of IBU. The bioavailability was high, indicating limited pre-systemic biotransformation. The AUC ratio of 2OH-IBU and COOH-IBU/IBU showed a significant increase at 4 weeks of age compared to the 1-week-old and 6- to 7-month-old pigs. Interestingly, the IBU-GlcA/IBU AUC ratio did not change with age. The present study demonstrated that the main metabolites of IBU in human are also present in growing pigs. The oxidative phase I metabolism of IBU in growing conventional pigs did change with age. In contrast, age did not seem to affect the glucuronidation capacity of IBU in conventional pigs, although more studies with other substrate drugs are needed to confirm this.

Highlights

Nowadays, the pig is being generally accepted as a preclinical animal model to predict the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a drug
Good correlation between analyte concentrations and detected responses was demonstrated for all three compounds, which was reflected in good correlation coefficients (r) that were higher than 0.99 and gof coefficients ranging between 3.16% and 5.67%, which were lower than the maximum acceptance criterion of 10%
The current study provides evidence that the same metabolites are formed in the conventional pig at different ages, suggesting the presence of similar biotransformation pathways

Summary

Introduction

The pig is being generally accepted as a preclinical animal model to predict the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a drug. This is attributed to the great anatomical and physiological similarities with human regarding the organs involved in absorption, distribution, metabolism, and excretion (ADME) of a drug The juvenile pig has been suggested as a possible animal model for the child. Several studies have already demonstrated the good similarities in PK characteristics between the piglet and the child (Roth et al, 2013; Gasthuys et al, 2018). Comparative data between human and pig are still largely lacking for the ADME processes, especially in the pediatric population

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