Gastric emptying and intestinal appearance of nonabsorbable drugs phenol red and paromomycin in human subjects: A multi-compartment stomach approach

Abstract

The goal of this study was to create a mass transport model (MTM) model for gastric emptying and upper gastrointestinal (GI) appearance that can capture the in vivo concentration-time profiles of the nonabsorbable drug phenol red in solution in the stomach and upper small intestine by direct luminal measurement while simultaneously recording the contractile activity (motility) via manometry. We advanced from a one-compartmental design of the stomach to a much more appropriate, multi-compartmental 'mixing tank' gastric model that reflects drug distribution along the different regions of the stomach as a consequence of randomly dosing relative to the different contractile phases of the migrating motor complex (MMC). To capture the intraluminal phenol red concentrations in the different segments of the GI tract both in fasted and fed state conditions, it was essential to include a bypass flow compartment ('magenstrasse') to facilitate the transport of the phenol red solution directly to the duodenum (fasted state) or antrum (fed state). The fasted and fed state models were validated with external reference data from an independent aspiration study using another nonabsorbable marker (paromomycin). These results will be essential for the development and optimization of computational programs for GI simulation and absorption prediction, providing a realistic gastric physiologically-based pharmacokinetic (PBPK) model based on direct measurement of gastric concentrations of the drug in the stomach.

Keywords: Aspiration/motility study; Bioavailability; Bioequivalence; Gastrointestinal; Gastrointestinal mass transport model; Human gastric emptying; In vivo dissolution; Nonabsorbable marker; Oral absorption; Paromomycin; Phenol red.

Fig. 1.

Different segments of the upper GI tract, representing the fundus, body and antrum (i.e., the stomach) followed by the transfer to the duodenum (i.e., the upper small intestine).

Fig. 2.

Representative illustration of the MTM of ‘Model 1’ that consists of three reactors in series representing the stomach, duodenum and jejunum, respectively. C_a0 stands for the initial concentration of phenol red present in the glass of water; Q₀ stands for the input flow (namely 250 mL in 2 min); R_wD and R_wJ stands for the secretion rate constants in the duodenum and jejunum, respectively; K_aw represents the water absorption rate constants, present in the duodenum and jejunum; KtD and KtJ are the first-order transit rate constants in the duodenum and jejunum, respectively.

Fig. 3.

Representative illustration of the MTM of ‘Model 8’ that consists of a body and antrum in series and a bypass compartment. Duodenum and jejunum reactors are connected in series with the stomach compartment. The bypass compartment can directly empty the administered solution of phenol red into the duodenum. C_a0 stands for the initial given dose of phenol red present in the glass of water; Q₀ stands for the input flow (namely 250 mL in 2 min); R_wD and R_wJ stands for the secretion rate constants in the duodenum and jejunum, respectively; K_aw represents the water absorption rate constants, present in the duodenum and jejunum; KtD and KtJ are the first-order transit rate constants in the duodenum and jejunum, respectively.

Fig. 4.

Representative illustration of the MTM of ‘Model 10’ that consists of a body and antrum in series and a bypass compartment that can transfer the phenol red solution directly to the antrum. Duodenum and jejunum reactors are connected in series with the stomach compartment. C_a0 stands for the initial concentration of phenol red present in the glass of water; Q₀ stands for input water flow i.e., 250 mL in 2 min; R_wD and R_wJ stands for the secretion rate constants in the duodenum and jejunum, respectively; K_aw represents the water absorption rate constants, present in the duodenum and jejunum; KtD and KtJ are the first-order transit rate constants in the duodenum and jejunum, respectively.

Fig. 5.

Average in vivo (n = 13; mean + SD) and adjusted concentration-time profiles of phenol red for all subjects in the stomach, duodenum and jejunum using Model 1.

Fig. 6.

Observed and simulated average and individual fasted state concentration-time profiles of phenol red as a function of time. Stomach concentrations refer to the concentrations measured (in vivo) and simulated (in silico) in the antrum. Adjusted values were derived from the simulations of model 8.

Fig. 7.

The bypassed fraction of phenol red for each subject as a function of the time when the first phase III contractions were observed post-dose.

Fig. 8.

Experimental and adjusted fasted state concentration-time profiles of paromomycin as a function of time. Applied values were derived from the adjustments of Model 8. Observed values are expressed as mean ± SEM (n = 5) and obtained from literature [13].

Fig. 9.

(A) Experimental and adjusted concentration-time profiles of paromomycin after oral administration of an immediate-release tablet of 250 mg of paromomycin during a phase I contractile activity. (B) Experimental and simulated concentration-time profiles of paromomycin after oral administration of an immediate-release tablet of 250 mg of paromomycin during a phase II contractile activity. All observed data were obtained from literature [11].

Fig. 10.

Average in vivo (n = 11; mean + SD) and adjusted concentration-time profiles of phenol red for all fed subjects in the stomach, duodenum and jejunum using Model 1. Observed data is presented as average + SD.

Fig. 11.

Observed and simulated average fed state concentration-time profiles of phenol red as a function of time. Stomach concentrations refer to the concentrations measured (in vivo) and simulated (in silico) in the antrum. Adjusted values were derived from the simulations of Model 10.

Fig. 12.

Experimental and simulated fed state concentration-time profiles of paromomycin as a function of time. Applied values were derived from the adjustments of Model 10. Observed values are expressed as mean ± SEM (n = 5) and obtained from Hens et al. [13].