Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological pharmacokinetic modeling

Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extr...

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Published inDrug metabolism and pharmacokinetics Vol. 35; no. 6; pp. 505 - 514
Main Authors Ito, Satoshi, Kamimura, Hidetaka, Yamamoto, Yousuke, Chijiwa, Hiroyuki, Okuzono, Takeshi, Suemizu, Hiroshi, Yamazaki, Hiroshi
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 01.12.2020
Subjects
Humanized chimeric mouse
Pharmacokinetic modeling
Prediction
Troglitazone
Troglitazone sulfate
Troglitazone sulfate
Humanized chimeric mouse
Pharmacokinetic modeling
Troglitazone
Prediction
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Abstract Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological pharmacokinetic modeling using pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK modeling proved to be a useful tool in understanding the function of each PK parameter in human pharmacokinetics of troglitazone and its conjugated metabolite. [Display omitted]
AbstractList Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological pharmacokinetic modeling using pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK modeling proved to be a useful tool in understanding the function of each PK parameter in human pharmacokinetics of troglitazone and its conjugated metabolite.
Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological pharmacokinetic modeling using pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK modeling proved to be a useful tool in understanding the function of each PK parameter in human pharmacokinetics of troglitazone and its conjugated metabolite. [Display omitted]
Author Kamimura, Hidetaka
Suemizu, Hiroshi
Yamazaki, Hiroshi
Okuzono, Takeshi
Yamamoto, Yousuke
Chijiwa, Hiroyuki
Ito, Satoshi
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  surname: Yamazaki
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  organization: Showa Pharmaceutical University, Machida, Tokyo, Japan
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32962912$$D View this record in MEDLINE/PubMed
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Keywords Troglitazone sulfate
Humanized chimeric mouse
Pharmacokinetic modeling
Troglitazone
Prediction
Language English
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Snippet Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human...
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pubmed
elsevier
SourceType Aggregation Database
Index Database
Publisher
StartPage 505
SubjectTerms Humanized chimeric mouse
Pharmacokinetic modeling
Prediction
Troglitazone
Troglitazone sulfate
Title Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological pharmacokinetic modeling
URI https://dx.doi.org/10.1016/j.dmpk.2020.07.004
https://www.ncbi.nlm.nih.gov/pubmed/32962912
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