Abstract:
BACKGROUND AND OBJECTIVES:Acetaminophen (APAP, paracetamol) is currently the principal cause of acute liver failure in both the USA and the UK. However, relatively little is known about the influence of genes and race/ethnicity on the disposition of APAP and the extent to which genetic variation and ethnicity may predispose individuals to a higher risk of APAP-induced hepatotoxicity. The objective of this research was to develop subpopulation-specific physiologically based pharmacokinetic (PBPK) models for two genetically different groups (Western Europeans and East Asians) and then use the models to quantify the difference in absorption, distribution, metabolism, and excretion (ADME) of APAP between these groups. METHODS:A comprehensive set of human pharmacokinetic data mined from the literature was divided into two groups based on ethnicity as an indicator of the expected abundance of phenol-metabolizing alleles. Using these datasets and a Bayesian hierarchical framework, subpopulation-specific physiologically based pharmacokinetic models for APAP were developed and tested for the two groups. RESULTS:Model simulations were in good agreement with experimental data for both time-dependent parent and metabolite concentrations and summary pharmacokinetic parameters. In addition, simulations were conducted to characterize the difference between ADME in these groups with regard to urinary excretion and APAP area under the curve (AUC) in the liver. Although not dramatic at therapeutic dosing levels, these results demonstrated the divergence in the liver-specific APAP concentrations and AUC between the two groups and suggested that differences in glucuronidation capacity may play a role in this disparity. CONCLUSIONS:Overall, the models developed in this study, and others created using this type of hierarchical methodology, are expected to be useful in quantifying ADME in a subpopulation-specific manner and reducing prediction uncertainty compared to that from generalized PBPK modeling approaches.
journal_name
Eur J Drug Metab Pharmacokinetjournal_title
European journal of drug metabolism and pharmacokineticsauthors
Zurlinden TJ,Reisfeld Bdoi
10.1007/s13318-016-0329-2subject
Has Abstractpub_date
2017-02-01 00:00:00pages
143-153issue
1eissn
0378-7966issn
2107-0180pii
10.1007/s13318-016-0329-2journal_volume
42pub_type
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journal_title:European journal of drug metabolism and pharmacokinetics
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abstract::A new high performance liquid chromatographic procedure has been developed for the simultaneous quantification of piribedil (PD) and its three main basic metabolites in rat plasma and urine, without and after hydrolysis. The procedure relies on isolation of the compounds from plasma and urine constituents using the Se...
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abstract::Influence of two newly synthesized bile acids derivates, namely sodium salt of monoketocholic acid MKH-Na and methyl ester of monoketocholic acid MKH-Me on tramadol (12.5 mg/kg oral and intramuscular) analgesic effect was examined in this research. Analgesic effect was measured by antinociceptive hot plate method. Int...
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journal_title:European journal of drug metabolism and pharmacokinetics
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journal_title:European journal of drug metabolism and pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::SC-46264 is an antagonist of the alpha 2-adrenergic receptor. Distribution and excretion of [14C]-SC-46264 were studied after single and repeated daily oral administrations to the Cynomolgus monkey at a 1.5 mg/kg dose. After a single oral administration, more than 95% of the administered dose was recovered within 48 h...
journal_title:European journal of drug metabolism and pharmacokinetics
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journal_title:European journal of drug metabolism and pharmacokinetics
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更新日期:1991-01-01 00:00:00
abstract::The present study reports findings on the disposition of epirubicin after an intrahepato-arterial administration of the Lipiodol-drug complex, prepared by mixing the drug-aqueous phase with the iodized oil by ultra-sonification, in 14 patients with histologically proven hepatoma or hepatomegaly with serum alpha-fetopr...
journal_title:European journal of drug metabolism and pharmacokinetics
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doi:10.1007/BF03190149
更新日期:1992-07-01 00:00:00
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更新日期:2009-07-01 00:00:00
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journal_title:European journal of drug metabolism and pharmacokinetics
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