![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmacy, University of Manchester (P.D.W., J.B.H.)
and
International Development Support (A.B.), Glaxo Wellcome
The time course for distribution of five compounds (caffeine,
tolbutamide, phenytoin, ondansetron, and diazepam) was studied in
precision-cut rat liver slices. Transport of these compounds differed
greatly, with caffeine being distributed rapidly, but not accumulating
above the media concentration. Although tolbutamide similarly was not
accumulated within the tissue, its uptake rate was slower. The rate of
phenytoin, ondansetron, and diazepam distribution (with appropriate
corrections for metabolism) was slower still; yet, these drugs were
accumulated within the cells of the slice to a concentration ~15-fold
that of the media. Examination of the physicochemical properties of
these compounds demonstrated that the extent of accumulation positively
correlated with lipophilicity, whereas the rate of uptake was not
statistically correlated with log D.
The extent of accumulation within the slice was assessed by an apparent
volume of distribution parameter (ranging from 26 to 195 µl/slice).
Using cell:media partition coefficients determined in hepatocytes and
the intra- and extracellular spaces within the slice (as measured with
the markers tritiated water and sucrose), it was possible to predict
apparent volumes of distribution for each drug in the liver slice.
Comparison of observed and predicted apparent volumes of distribution
gave ratios of 0.34-1. Intrinsic clearance values for these five drugs
are available for slices and cells (slice:cell intrinsic clearance
ratios 0.05-0.43; Worboys et al., Drug Metab.
Dispos. 24, 676-681, 1996). Drugs that demonstrate low intrinsic
clearance ratios also have low apparent volume ratios, thus indicating
that reduced drug uptake and clearance in slices, relative to
hepatocytes, are interdependent. Both phenomena may be rationalized by
the existence of a drug concentration gradient within the slice. At
very high drug concentrations, Vmax operates, and the consequence of the gradient is minimal. Therefore, it is
possible to speculate upon the fraction of hepatocytes within the slice
contributing to clearance by considering Vmax
values. For six pathways of metabolism, Vmax in
slices averages 35% of the corresponding parameter in isolated
hepatocytes. This is most likely due to limited oxygen and compromised
metabolic function of the core cells. These distribution phenomena
severely complicate the possibility of using a scaling factor based on
the theoretical number of slices obtainable from a liver to predict
in vivo intrinsic clearance.
This article has been cited by other articles:
|
|
 |
|
  J. R. Atack, A. Pike, A. Clarke, S. M. Cook, B. Sohal, R. M. McKernan, and G. R. Dawson RAT PHARMACOKINETICS AND PHARMACODYNAMICS OF A SUSTAINED RELEASE FORMULATION OF THE GABAA {alpha}5-SELECTIVE COMPOUND L-655,708 Drug Metab. Dispos., May 1, 2006; 34(5): 887 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. M. de Graaf, R. de Kanter, M. H. de Jager, R. Camacho, E. Langenkamp, E. G. van de Kerkhof, and G. M. M. Groothuis EMPIRICAL VALIDATION OF A RAT IN VITRO ORGAN SLICE MODEL AS A TOOL FOR IN VIVO CLEARANCE PREDICTION Drug Metab. Dispos., April 1, 2006; 34(4): 591 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Griffin and J. B. Houston PREDICTION OF IN VITRO INTRINSIC CLEARANCE FROM HEPATOCYTES: COMPARISON OF SUSPENSIONS AND MONOLAYER CULTURES Drug Metab. Dispos., January 1, 2005; 33(1): 115 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Haenen, C. Rompelberg, K. van Twillert, M. Hamzink, J. Dormans, and J. van Eijkeren Utility of Rat Liver Slices to Estimate Hepatic Clearance for Application in Physiologically Based Pharmacokinetic Modeling: A Study with Tolbutamide, a Compound with Low Extraction Efficiency Drug Metab. Dispos., March 1, 2002; 30(3): 307 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Thohan, M. C. Zurich, H. Chung, M. Weiner, A. S. Kane, and G. M. Rosen Tissue Slices Revisited: Evaluation and Development of a Short-Term Incubation for Integrated Drug Metabolism Drug Metab. Dispos., October 1, 2001; 29(10): 1337 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. MacGregor, J. M. Collins, Y. Sugiyama, C. A. Tyson, J. Dean, L. Smith, M. Andersen, R. D. Curren, J. B. Houston, F. F. Kadlubar, et al. In Vitro Human Tissue Models in Risk Assessment: Report of a Consensus-Building Workshop Toxicol. Sci., January 1, 2001; 59(1): 17 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. T. Jewell and M. G. Miller Comparison of Human and Rat Metabolism of Molinate in Liver Microsomes and Slices Drug Metab. Dispos., July 1, 1999; 27(7): 842 - 847. [Abstract] [Full Text]
|
|
|
|
|
|
D. J. Carlile, N. Hakooz, and J. B. Houston Kinetics of Drug Metabolism in Rat Liver Slices: IV. Comparison of Ethoxycoumarin Clearance by Liver Slices, Isolated Hepatocytes, and Hepatic Microsomes from Rats Pretreated with Known Modifiers of Cytochrome P-450 Activity Drug Metab. Dispos., April 1, 1999; 27(4): 526 - 532. [Abstract] [Full Text]
|
|
|
|
|
|
M. VandenBranden, S. A. Wrighton, S. Ekins, J. S. Gillespie, S. N. Binkley, B. J. Ring, M. G. Gadberry, D. C. Mullins, S. C. Strom, and C. B. Jensen Alterations of the Catalytic Activities of Drug-Metabolizing Enzymes in Cultures of Human Liver Slices Drug Metab. Dispos., November 1, 1998; 26(11): 1063 - 1068. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
