Steady-State Human Pharmacokinetics of Monobutyl Phthalate Predicted by Physiologically Based Pharmacokinetic Modeling Using Single-Dose Data from Humanized-Liver Mice Orally Administered with Dibutyl Phthalate

Abstract

Dibutyl phthalate (DBP) was widely used as a plasticizer but it has been recently replaced with other kinds of phthalates such as di(2-ethylhexyl)phthalate and diisononyl phthalate because of its toxicity. To evaluate the human risk of DBP, forward and reverse dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling based on in vivo experimental pharmacokinetic data in humanized-liver mice (HL-mice) obtained after an oral dose of 100 mg/kg. Absorbed DBP was converted to monobutyl phthalate (MBP) and its glucuronide extensively in vivo. HL-mice had higher concentrations of MBP glucuronide in plasma than did the control mice. Concentrations of MBP glucuronide in 0−7 h accumulated urine samples from HL-mice were significantly higher than those in control mice. Similarly, in vitro MBP glucuronidation rates mediated by pooled microsomes from rat or mouse livers were lower than those mediated by human liver microsomes. Liver damage by MBP to humanized liver was detected by measuring human albumin mRNA in HL-mouse plasma. By simple PBPK modeling, in silico concentration curves in plasma, liver, or urine following virtual oral administration of DBP were created for rats, control mice, and HL-mice. A human PBPK model for MBP was established based on the HL-mouse PBPK model using allometric scaling without consideration of interspecies factors in terms of liver metabolism. Human PBPK models were used to estimate urinary and plasma concentrations of MBP and its glucuronide throughout 14 days of oral DBP administration (1.2 and 13 μg/kg/day). Reverse dosimetry PBPK modeling found that reported 50th and 95th percentile MBP urine and plasma concentrations of the general population could potentially imply exposures similar to or exceeding tolerable daily intake levels (5−10 μg/kg/day) recommended by the European and Japanese authorities. Further in-depth assessment of DBP is needed to assess the validity of assumptions made based on human biomonitoring data.

Differences in Pharmacokinetics and Haematotoxicities of Aniline and Its Dimethyl Derivatives Orally Administered in Rats

“…Simplified rat PBPK models consisting of gut, liver, kidney, and central compartments were set up for aniline and its dimethyl derivatives 10,17) . The values of the plasma unbound fraction (f u,p ), octanol-water partition coefficient (logP), blood-to-plasma concentration ratio (R b ), and the liver-to-plasma or kidney-to-plasma concentration ratio (K p,h or K p,r ) for aniline and its dimethyl derivatives were calculated using in silico tools (Simcyp and ChemDraw software) as described previously 18,19) ; the results are shown in Table 1.…”

“…The values of the plasma unbound fraction (f u,p ), octanol-water partition coefficient (logP), blood-to-plasma concentration ratio (R b ), and the liver-to-plasma or kidney-to-plasma concentration ratio (K p,h or K p,r ) for aniline and its dimethyl derivatives were calculated using in silico tools (Simcyp and ChemDraw software) as described previously 18,19) ; the results are shown in Table 1. The values used for the hepatic and renal blood flow rates (Q h and Q r ) in rats were 0.853 L/h, and hepatic and renal volumes of 8.5 mL (8.5 g) and 3.7 mL (3.7 g), respectively, were used as described previously 10,17) . Initial values for the fraction absorbed × intestinal availability (F a •F g ), the hepatic clearance (CL h ), and the renal clearance (CL r ) for PBPK modelling were derived from the elimination constants obtained using one-compartment models.…”

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

“…The molecular weights (258, 274, and 274), octanol-water partition coefficients (clogP; 0.528, -0.138, and 0.402), plasma unbound fractions (f u,p ; 0.588, 0.615, and 0.237), and blood-plasma concentration ratios (R b ; 0.893, 0.885, and 0.904) of thalidomide, 5′-hydroxythalidomide, and 5-hydroxythalidomide, respectively, were used as described previously (Nishiyama et al, 2015;Yamazaki et al, 2012). The values used for the hepatic and renal blood flow rates (Q h and Q r ) in rats were 0.853 L/hr, and the hepatic and renal volumes (V h and V r ) of 8.5 mL and 3.7 mL, respectively, as described previously (Miura et al, 2019a). The initial values for the fraction absorbed × intestinal availability (F a •F g ), the hepatic clearance (CL h ), and the renal clearance (CL r ) for PBPK modeling were derived from the elimination constants obtained using one-compartment models (Miura et al, 2019a).…”

“…The values used for the hepatic and renal blood flow rates (Q h and Q r ) in rats were 0.853 L/hr, and the hepatic and renal volumes (V h and V r ) of 8.5 mL and 3.7 mL, respectively, as described previously (Miura et al, 2019a). The initial values for the fraction absorbed × intestinal availability (F a •F g ), the hepatic clearance (CL h ), and the renal clearance (CL r ) for PBPK modeling were derived from the elimination constants obtained using one-compartment models (Miura et al, 2019a).…”

Metabolic profiles for the pyrrolizidine alkaloid neopetasitenine and its metabolite petasitenine in humans extrapolated from rat <i>in vivo</i> and <i>in vitro</i> data sets using a simplified physiologically based pharmacokinetic model

“…1A). To underline the effectiveness and simplicity of PBPK models compared with complicated full multiple-compartment models, we created a simplified modeling system that uses a mixture of algorithms utilizing empirical data and/or literature resources (Kamiya et al, 2019(Kamiya et al, , 2020aMiura et al, 2019aMiura et al, , 2019b.…”