Cationic Drug Pharmacokinetics in Diseased Livers Determined by Fibrosis Index, Hepatic Protein Content, Microsomal Activity, and Nature of Drug

Abstract

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl 4 )-induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic ␣ 1 -acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P app ) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl 4 -treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeabilitysurface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k in ) and efflux rate constant (k out ), and k in /k out were related to physicochemical properties of drug (log P app or pK a ) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver

“…4) are consistent with correlations we found for cationic drug hepatocyte permeability/surface area product with fibrosis index. 9 Further, others have suggested that fibrosis may be rate limiting in the hepatocellular uptake of other nutrients such as oxygen. 21 It is concluded that a mixture of 2 inverse gaussian density functions and a barrier-limited and space-distributed liver model adequately described the alterations of hepatic microcirculation in control and diseased animal models.…”

“…23 It has been shown that computerized imaging enables a precise quantification of fibrosis, and we have used this technique in a recent investigation of the effects of liver disease on cationic drug pharmacokinetics. 9 A number of studies have related MID estimated clearances in the fibrotic rat liver to changes in hepatic microcirculation. [5][6][7]13,[28][29][30][31] In this study, we examined the interrelationships between hepatic extraction, hepatic fibrosis, and changes in vascular spaces for CCl 4 -treated, alcoholtreated and normal rat livers.…”

“…The alcohol rat model was developed using a procedure described previously. 9,[14][15][16] Briefly, male Wistar rats (each weighing approximately 150 g) were housed in individual cages. In group 1, rats (n ϭ 6) were fed a nutritionally high-fat liquid alcohol diet (Dyets, Bethlehem, PA) containing ethanol (36% of the total caloric intake) for 12 weeks.…”

“…The CCl 4 rat model was established following a procedure previously outlined in detail. 1,9,[11][12][13] Briefly, male Wistar rats (weighing approximately 150 g) were caged in groups of 6 each (2 groups) and given 35 mg/dL sodium phenobarbital (Biotech Int, Ltd., Rocklea, Australia) in their drinking water ad libitum; the first dose of CCl 4 was administered 10 days later. In group 1, animals were given CCl 4 (Sigma Chemical Co., St. Louis, MO) once a week for 12 weeks.…”

“…9 In this case, cationic drug disposition in the fibrotic liver can be predicted from drug properties and liver histopathology. As a result, the question was raised of whether we could use histopathology from patient liver biopsy specimens to estimate changes in hepatic spaces and whether the active and passive transport of probes (e.g., 3 H-taurocholate, 3 H-water) across the liver plasma membrane could be related to the severity of fibrosis.…”