Document Detail


Interaction between HIV protease inhibitors (PIs) and hepatic transporters in sandwich cultured human hepatocytes: implication for PI-based DDIs.
MedLine Citation:
PMID:  23280499     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although HIV protease inhibitors (PIs) produce profound metabolic interactions through inactivation/inhibition of CYP3A enzymes, their role as victims of transporter-based drug-drug interactions (DDIs) is less well understood. Therefore, this study investigated if the PIs, nelfinavir (NFV), ritonavir (RTV), lopinavir (LPV) or amprenavir (APV) were transported into sandwich-cultured human hepatocytes (SCHH), and whether OATPs contributed to this transport. The findings showed that, except for (3) H-APV, no significant decrease in the total hepatocyte accumulation of the (3) H-PIs was detected in the presence of the corresponding unlabeled PI, indicating that the uptake of the other PIs was not mediated. Further, hepatocyte biliary efflux studies using (3) H-APV and unlabeled APV confirmed this decrease to be due to inhibition of sinusoidal influx transporter(s) and not the canalicular efflux transporters. Moreover, this sinusoidal transport of APV was not OATP-mediated. The results indicate that the hepatic uptake of NFV, RTV or LPV was primarily mediated by passive diffusion. The hepatic uptake of APV was mediated by an unidentified sinusoidal transporter(s). Therefore, NFV, RTV or LPV will not be victims of DDIs involving inhibition of hepatic influx transporters; however, the disposition of APV may be affected if its sinusoidal transport is inhibited.
Authors:
Li Liu; Jashvant D Unadkat
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-04
Journal Detail:
Title:  Biopharmaceutics & drug disposition     Volume:  34     ISSN:  1099-081X     ISO Abbreviation:  Biopharm Drug Dispos     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-12     Completed Date:  2013-09-24     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  7911226     Medline TA:  Biopharm Drug Dispos     Country:  England    
Other Details:
Languages:  eng     Pagination:  155-64     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Carbamates / metabolism
Cells, Cultured
Drug Interactions
HIV Protease Inhibitors / metabolism*
Hepatocytes / metabolism*
Humans
Lopinavir / metabolism
Nelfinavir / metabolism
Organic Anion Transporters / metabolism*
Ritonavir / metabolism
Sulfonamides / metabolism
Grant Support
ID/Acronym/Agency:
GM032165/GM/NIGMS NIH HHS; P01 GM032165/GM/NIGMS NIH HHS; RCNS06804//PHS HHS; TL1 TR000422/TR/NCATS NIH HHS; TL1-RR025016/RR/NCRR NIH HHS; UL1 TR000423/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Carbamates; 0/HIV Protease Inhibitors; 0/Organic Anion Transporters; 0/Sulfonamides; 161814-49-9/amprenavir; 2494G1JF75/Lopinavir; HO3OGH5D7I/Nelfinavir; O3J8G9O825/Ritonavir
Comments/Corrections

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