Abstract
Phenol red (PR) is a widely used marker for water flux correction in studies of in situ perfusion, in which intestinal absorption usually leads to the underestimation of results. In this paper, we propose a novel marker polyethylene glycol (PEG)-PR (i.e., PR modified by PEGylation) with less permeability and evaluate its application in an in situ perfusion model in rats. PEG-PR was synthesized by the chemical conjunction of polyethylene glycol-4k/5k (PEG-4k/5k) and PR. The synthesized PEG-PR was then characterized using 1H-NMR, 13C-NMR, ultraviolet (UV), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) analyses. The low permeability of PEG-PR was assessed using everted gut sac (EGS) methods. The apparent permeability coefficients (Papp, 3–8 × 10−7 cm/s) of PEG4k/5k-PR exhibited a nearly 15-fold reduction compared to that of PR. The different concentrations of PEG4k/5k-PR did not contribute to the Papp value or cumulative permeable percentage (about 0.02–0.06%). Furthermore, the larger molecular weight due to PEGylation (PEG5k-PR) enhanced the nonabsorbable effect. To evaluate the potential application of the novel marker, atenolol, ketoprofen, and metoprolol, which represent various biopharmaceutics classification system (BCS) classes, were selected as model drugs for the recirculation perfusion method. The water flux corrected by PEG4k/5k-PR reflected the accuracy due to the nonabsorbable effect, while the effective intestinal membrane permeability (Peff) of atenolol corrected by PEG4k/5k-PR showed a statistically significant increase (p < 0.05) in different intestinal segments. In conclusion, PEG-PR is a promising marker for the permeability estimation when using the in situ perfusion model in rats.
Highlights
Oral administration remains a priority for drug delivery
The polyethylene glycol (PEG)-Ts intermediate was synthesized through a nucleophilic substitution reaction between
The conversion ratio was calculated by comparing the integrals of the aromatic proton peak at peak at δ 7.35–7.82 ppm of toluenesulfonyl chloride (TsCl) with the methoxy proton peak at δ 3.40 ppm of PEG
Summary
Multiple factors contribute to the complexity of this process, recent developments in biopharmaceutics classification system (BCS) theory have recognized two key parameters—the solubility and intestinal permeability of a drug—that govern the fraction of dose absorbed (Fabs ) [1]. As they have been widely accepted and applied in academic research and industrial regulations, the important status of these two parameters is evident [2]. Molecules 2020, 25, 5123 trials has driven the development of various models to predict the human intestinal absorption of drugs [4,5,6,7]. The in situ perfusion model in rats has been considered as an optimal alternative for drug permeability estimation, as it can preserve the real and bioactive intestinal environment to the utmost extent—something which other in vitro modeling techniques
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