Abstract
To elucidate the transport system by which [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) is taken up into the liver, we investigated the uptake characteristics of Z-335 in isolated rat hepatocytes. In addition, we estimated the hepatic uptake of Z-335 in intact rats under steady-state conditions and compared it with the in vitro uptake clearance. Uptake of Z-335 is highly concentrative (cell-to-medium concentration ratios were 21.2 at 0.5 min and 71.7 at 5 min), temperature-dependent, and sensitive to metabolic inhibitors, indicating that uptake is mediated by energy-dependent uphill transport. In the presence of metabolic inhibitors [carbonyl cyanidep-trifluoromethoxyphenylhydrazone and rotenone], uptake remained at 37 and 49% of the control value, respectively, suggesting that ATP-independent uptake contributes to the total uptake of Z-335. The concentration dependence of the initial uptake velocity indicated a two-component process, one saturable component, with aKm value of 45.6 μM and aVmax value of 4.1 nmol/min/mg of protein, and a nonspecific diffusion clearance, with aPdif value of 8.3 μl/min/mg of protein. The contribution of the carrier-mediated uptake to the total uptake in a linear range was estimated as 91%. The in vivo hepatic intrinsic clearance (CLint, app) was comparable with that in vitro uptake clearance (PSinflux) and indicated that the CLint, app of Z-335 at steady state is rate-limited by the uptake process. In conclusion, hepatic intrinsic clearance of Z-335 at steady state is rate-limited by the uptake process since Z-335 is efficiently taken up by an active transport mechanism, followed by metabolism or biliary excretion.
Footnotes
- Abbreviations used are::
- Z-335
- [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate
- TXA2
- thromboxane A2
- SQ-29548
- 1S-[1α,2β(5Z),3β,4α]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
- U-46619
- 11,9 epoxymethano-prostaglandin H2
- oatp
- organic anion transporting polypeptide
- ID910096
- sodium [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]ethylcarboxylate
- FCCP
- carbonyl cyanidep-trifluoromethoxyphenylhydrazone
- BSP
- bromosulfophthalein
- C/M ratio
- cell-to-medium concentration ratio
- PSinflux
- permeability-surface product
- CL
- clearance
- oat
- organic anion transporter
- Received September 14, 2001.
- Accepted January 18, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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