Metabolic disposition of tacrine in primary suspensions of rat hepatocyte and in single-pass perfused liver: In vitro/in vivo comparisons

Article abstract of DOI:10.3109/00498259409038670

1. Incubations of tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate, THA) with a primary suspension of rat hepatocytes for 2 min resulted in formation of the 1-hydroxy derivative as the major metabolite with smaller amounts of the 2- and 4-hydroxy metabolites. 2. Apparent V(max) and K(m) for THA metabolism were 12.4 ± 3.3 nmol/min/g liver and 0.98 ± 0.34 μM respectively. 3. Incubations of THA for longer time-periods (> 10 min) resulted in irreversible binding of THA-derived radioactivity to hepatocellular protein. The apparent maximal rate of irreversible binding (B(max)) was 76.7 ± 30.5 pmol equivalents bound/h/mg cell protein, whereas the apparent K(b) for binding was 2.8 ± 1.4 μM. 4. The kinetic parameters, V(max) and K(m), were used to predict steady-state extraction ratios (ER(SS)) for various THA input concentrations (C(in)) in single-pass perfused rat liver. At low input concentrations (0.72-0.85 μM; C(in) < K(m)), ER(SS) of THA was approximately 1. For higher C(in) (14.05, 20.72, 20.88 μM; C(in) ≥ K(m)), the calculated ER(SS) was markedly decreased with 0.300, 0.296 and 0.261, respectively. 5. The intrinsic clearance of THA (Cl(i)) estimated from in vitro hepatocyte data was 6.7 ml/min/g liver while the apparent oral THA clearance (Cl(oral)) calculated from in vivo rat data was 6.6 ml/min/g liver.

Full text of DOI:10.3109/00498259409038670

Xenobiotica
the fate of foreign compounds in biological systems
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
Metabolic disposition of tacrine in primary
suspensions of rat hepatocyte and in single-pass
perfused liver: in vitro/in vivo comparisons
M. Kukan, Š. Bezek, W. F. Pool & T. F. Woolf
To cite this article: M. Kukan, Š. Bezek, W. F. Pool & T. F. Woolf (1994) Metabolic disposition of
tacrine in primary suspensions of rat hepatocyte and in single-pass perfused liver: in vitro/in
vivo comparisons, Xenobiotica, 24:11, 1107-1117
To link to this article: http://dx.doi.org/10.3109/00498259409038670
Published online: 27 Aug 2009.
Submit your article to this journal
Article views: 9
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ixen20
Download by: [University of California Santa Barbara]
Date: 06 November 2015, At: 12:27