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Development of a physiologically based pharmacokinetic model for benzyl butyl phthalate and its active metabolites, mono benzyl phthalate and mono butyl phthalate, in rats
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Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S22eS26
skin, intestine, pancreatic islets or neuronal tissues). In addition we present a new 4-Organ-Chip (4-OC) platform for ADME profiling. In this 4Organ-Chip platform, a human primary intestinal model and a skin biopsy have been integrated on standard cell culture inserts. A fluid flow connected these barrier models with a 3D-based liver spheroid. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. It could be shown, that our Multi-Organ-Chip is universally applicable to co-culture different organ models over a culture period of up to 28 days. Tissue engineering data and assay performance data for repeated dose substance exposures through topical, apical and systemic administration routes will be presented. 4-OC results showed steady homeostasis during the complete culture period. Hence, a unique Multi-Organ-Chip platform was developed, enabling the testing of effects of substances on a set of miniaturized human organs. A12 DEVELOPMENT MODEL FOR METABOLITES, PHTHALATE, IN
OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC BENZYL BUTYL PHTHALATE AND ITS ACTIVE MONO BENZYL PHTHALATE AND MONO BUTYL RATS
Min Gi Kim, Hyeon Gwan Choi, Youngsung Lee, Junwoo Park, Sungwook Park, Sun Dong Yoo. Sungkyunkwan University, Suwon, South Korea Benzyl butyl phthalate (BBP) is a plasticizer widely used to increase the flexibility of PVCs. It induces various toxicities in experimental animals including the endocrine disrupting activity. When ingested, BBP is metabolized in the gut to mono benzyl phthalate (MBzP) and mono butyl phthalate (MBuP) which are known to cause developmental and reproductive toxicities. The present study describes the development of a physiologically based pharmacokinetic (PBPK) model that can simultaneously describe the absorption and disposition pharmacokinetics of BBP and its major metabolites, MBzP and MBuP, in rats. The PBPK model
consisted of the BBP, MBzP and MBuP components linked to each other via liver, kidney, and blood compartments where the metabolic conversion of BBP to MBzP or MBuP takes place. Physiological parameters including the blood flow rates and the tissue weights obtained from the literature [1]. The pharmacokinetic parameters and the tissue-to-blood partition coefficients were obtained after intravenous injection and infusion experiments [2]. Other substances specific parameters were estimated by fitting the blood, urine and tissue concentration vs. time profiles observed after intravenous injection of each of these compounds. For model validation, BBP was given to rats by single and multiple intravenous injections. Blood and tissue samples were collected at 3.5, 4, 6.5, 7, 8, 9.5, 10 and 11 hr after initiation of the intravenous injection. The developed model was validated by comparing the simulated data with the observed data obtained after single intravenous injection (BBP 5 mg/kg) and multiple intravenous injections (BBP 10 mg/kg; t ¼ 3 hr). After a single bolus injection, the predicted plasma BBP concentrations were comparable with the observed concentrations (C0: 601.8 vs. 655.8 ng/ml; AUCinf: 100.1 vs. 121.8 ng$hr/ml). In addition, the simulated plasma and urine concentrations of metabolites were comparable with the observed data (Cmax: 1552.5 vs. 2056.6 ng/ml for MBzP, 4592.5 vs. 4307.6 ng/ml for MBuP; AUCinf: 1050.7 vs. 1299.1 ng$hr/ml for MBzP, 1658.7 vs. 1513.9 ng$hr/ml for MBuP; Fe, urine: 2.9 vs. 3.5% for MBzP, 13.4 vs. 10.4% for MBuP). After multiple intravenous injections, the simulated concentration-time profiles were in good agreement with the observed profiles of BBP, MBzP and MBuP in plasma and tissues. In summary, the developed PBPK model was successfully used to simultaneously describe the absorption, tissue distribution and elimination of BBP, MBzP and MBuP in rats. 1. Davies B. and Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993; 10:1093-1095. 2. Kim M.G., Kim T.H., Shin B.S., Lee Y.B., Lee J.B., Choi H.G., Lee Y., Yoo S.D. Sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous determination of benzyl butyl phthalate and its metabolites, monobenzyl phthalate and monobutyl phthalate, in rat plasma, urine, and various tissues collected from a toxicokinetic study. Anal Bioanal. Chem. 2015; 407:7391-7400.
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S22eS26
skin, intestine, pancreatic islets or neuronal tissues). In addition we present a new 4-Organ-Chip (4-OC) platform for ADME profiling. In this 4Organ-Chip platform, a human primary intestinal model and a skin biopsy have been integrated on standard cell culture inserts. A fluid flow connected these barrier models with a 3D-based liver spheroid. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. It could be shown, that our Multi-Organ-Chip is universally applicable to co-culture different organ models over a culture period of up to 28 days. Tissue engineering data and assay performance data for repeated dose substance exposures through topical, apical and systemic administration routes will be presented. 4-OC results showed steady homeostasis during the complete culture period. Hence, a unique Multi-Organ-Chip platform was developed, enabling the testing of effects of substances on a set of miniaturized human organs. A12 DEVELOPMENT MODEL FOR METABOLITES, PHTHALATE, IN
OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC BENZYL BUTYL PHTHALATE AND ITS ACTIVE MONO BENZYL PHTHALATE AND MONO BUTYL RATS
Min Gi Kim, Hyeon Gwan Choi, Youngsung Lee, Junwoo Park, Sungwook Park, Sun Dong Yoo. Sungkyunkwan University, Suwon, South Korea Benzyl butyl phthalate (BBP) is a plasticizer widely used to increase the flexibility of PVCs. It induces various toxicities in experimental animals including the endocrine disrupting activity. When ingested, BBP is metabolized in the gut to mono benzyl phthalate (MBzP) and mono butyl phthalate (MBuP) which are known to cause developmental and reproductive toxicities. The present study describes the development of a physiologically based pharmacokinetic (PBPK) model that can simultaneously describe the absorption and disposition pharmacokinetics of BBP and its major metabolites, MBzP and MBuP, in rats. The PBPK model
consisted of the BBP, MBzP and MBuP components linked to each other via liver, kidney, and blood compartments where the metabolic conversion of BBP to MBzP or MBuP takes place. Physiological parameters including the blood flow rates and the tissue weights obtained from the literature [1]. The pharmacokinetic parameters and the tissue-to-blood partition coefficients were obtained after intravenous injection and infusion experiments [2]. Other substances specific parameters were estimated by fitting the blood, urine and tissue concentration vs. time profiles observed after intravenous injection of each of these compounds. For model validation, BBP was given to rats by single and multiple intravenous injections. Blood and tissue samples were collected at 3.5, 4, 6.5, 7, 8, 9.5, 10 and 11 hr after initiation of the intravenous injection. The developed model was validated by comparing the simulated data with the observed data obtained after single intravenous injection (BBP 5 mg/kg) and multiple intravenous injections (BBP 10 mg/kg; t ¼ 3 hr). After a single bolus injection, the predicted plasma BBP concentrations were comparable with the observed concentrations (C0: 601.8 vs. 655.8 ng/ml; AUCinf: 100.1 vs. 121.8 ng$hr/ml). In addition, the simulated plasma and urine concentrations of metabolites were comparable with the observed data (Cmax: 1552.5 vs. 2056.6 ng/ml for MBzP, 4592.5 vs. 4307.6 ng/ml for MBuP; AUCinf: 1050.7 vs. 1299.1 ng$hr/ml for MBzP, 1658.7 vs. 1513.9 ng$hr/ml for MBuP; Fe, urine: 2.9 vs. 3.5% for MBzP, 13.4 vs. 10.4% for MBuP). After multiple intravenous injections, the simulated concentration-time profiles were in good agreement with the observed profiles of BBP, MBzP and MBuP in plasma and tissues. In summary, the developed PBPK model was successfully used to simultaneously describe the absorption, tissue distribution and elimination of BBP, MBzP and MBuP in rats. 1. Davies B. and Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993; 10:1093-1095. 2. Kim M.G., Kim T.H., Shin B.S., Lee Y.B., Lee J.B., Choi H.G., Lee Y., Yoo S.D. Sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous determination of benzyl butyl phthalate and its metabolites, monobenzyl phthalate and monobutyl phthalate, in rat plasma, urine, and various tissues collected from a toxicokinetic study. Anal Bioanal. Chem. 2015; 407:7391-7400.