First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans

Abstract

We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes.

Gut–liver on a chip toward an in vitro model of hepatic steatosis

“…In particular, interactions between the gut and the liver have been the focus of intense research (Chen et al, ; Choe, Ha, Choi, Choi, & Sung, ; D. W. Lee, Ha, Choi, & Sung, ). For example, Leclerc et al, developed a microfluidic gut–liver chip to study the first‐pass metabolism of drugs (Bricks et al, ; Prot et al, ). Similarly, van Midwoud, Merema, Verpoorte, and Groothuis () reported a perfusion culture device for gut and liver tissue slices, and observed the interaction between the two tissues.…”

Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing

“…(Prot et al, 2014). The results demonstrated paracetamol transport through the intestinal unit followed by synergistic metabolism via the production of paracetamol sulfate in both the liver and intestinal units.…”

Investigation of omeprazole and phenacetin first‐pass metabolism in humans using a microscale bioreactor and pharmacokinetic models

“…Hepatic availability is given by the following equation and is the relative quantity of phenacetin and omeprazole escaping liver metabolism [40]:…”

“…This scaling factor is based on the mass of intestine per kilogram of body mass (7.5 g per kg of body mass following the results of Lin et al [41]) and the number of enterocytes per gram of intestine (estimated to 250 × 10 6 enterocytes per 0.685 g of intestine [40]). The intestinal in vitro intrinsic clearances obtained from the model were also scaled into intestinal in vivo intrinsic clearances using a scaling factor SF2.…”

“…The intestinal in vitro intrinsic clearances obtained from the model were also scaled into intestinal in vivo intrinsic clearances using a scaling factor SF2. This scaling factor is based on the mass of intestine per kilogram of body mass (7.5 g per kg of body mass following the results of Lin et al [41]) and the number of enterocytes per gram of intestine (estimated to 250 × 10 6 enterocytes per 0.685 g of intestine [40]).…”