Hepatic uptake clearance

Miyauchi, S., Sawada, Y., Iga, T., Hanano, M., Sugiyama, Y., Comparison of the hepatic uptake clearances of fifteen drugs with a wide range of membrane permeabilities in isolated rat hepatocytes and perfused rat livers, Pharm. Res. 1993, 10, 434-440. 

Figure 19.3 summarizes two major clearances governing the biodistribution of most macromolecular drugs—the hepatic uptake clearance and the urinary excretion clearance-of model compounds with diverse... 

Figure 2 Comparison between the uptake clearance obtained in vivo and that extrapolated from the in vitro transport study of endothelin antagonists. In vivo uptake clearance of endothelin antagonists (BQ-123, BQ-518, BQ-485, compound A) was evaluated by integration plot analysis using the plasma concentration-time profile after intravenous administration (500 nmol/kg) and the amount of drug in the liver and that excreted in the bile. In vitro hepatic uptake clearance was measured using isolated rat hepatocytes and was extrapolated to the in vivo uptake clearance assuming the well-stirred model. Source From Ref. 5.

After intravenous administration in mice, pDNA is rapidly eliminated from the plasma due to extensive uptake into the liver as well as rapid degradation by nucleases, with hepatic uptake clearance approaching liver plasma flow. pDNA is preferentially taken up by liver non-parenchymal cells, such as KupfFer and endothelial cells via receptor-mediated processes [70]. 

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

Fig. 5.4 Model for the hepatic processes involved in the clearance of the combined TxSI/TxRAs (see Figure 5.3). The clearance by hepatic uptake (Clup) is the rate-determining step in the removal of the compound from the perfusate. Compounds accumulate within the liver and are subsequently cleared by biliary (Clbii) or metabolic clearance (CIm) (modified from reference [2]).

Inter-Species Scalingfor Clearance by Hepatic Uptake l29... 

Inter-Species Scaling for Clearance by Hepatic Uptake... 

Organic anions have frequently been implicated as substrates for transporters in the sinusoidal membrane of the liver. This was illustrated for a series of TxRAs, where hepatic uptake was identified as the rate-determining step in the clearance process [22]. A representative compound from this series, UK-147,535 (Figure 9.3), was progressed to clinical trials [23]. It is thus possible to contrast clearance of this compound between a number of species including man (Figure 9.4). 

Chylomicron metabolism. Smoke, administered to rats injected intravenously with C- and H-labeled chylomicrons, produced no difference in the initial plasma clearance time of labeled chylomicrons between smoke-treated and control animals. Hepatic uptake of chylomicron cholesterol was slower in smoke-treated animals than in controls. More labeled chylomicrons remained in the heart of smoke-treated rats than controls . 

The WHHL model has stimulated major advances in our understanding of apoB receptors (G22). In particular, it has allowed a clear differentiation of two kinds of hepatic receptors one involved in the uptake of chylomicron remnants, recognizing (it is thought) apoE when in a particle containing apoB-48, and the other involved in the hepatic uptake of apoB-100-contain-ing VLDL, IDL, and LDL particles. The apoB-100 receptors, which also have an affinity for apoE and are referred to in this review as apoB-100, E receptors, are found in many extrahepatic cells. The WHHL rabbit is deficient in apoB-100, E receptors, but not in those receptors responsible for chylomicron clearance. 

Cholestasis can prolong the action of pancuronium, reducing its plasma clearance by 50%. This may be a result of raised bile salts, reducing the hepatic uptake of pancuronium (which is an important factor contributing to the total plasma clearance in normal patients) (SEDA-6, 130). 

From animal investigations hepatic uptake appears to be a factor in the drug s total plasma clearance, but renal excretion seems to be the main route of elimination. Ligation of renal pedicles in dogs (3) resulted in reduced elimination of pipecuronium, with a four-fold increase in mean residence time and a four-fold increase in hepatobiliary elimination, which did not compensate for the loss of urinary excretion. In humans, about 40% of... 

Increased plasma bile acid concentrations in the fasting state suggest impaired hepatic uptake or secretion, or portosystemic shunting. Thus, such measurements may be used as a sensitive endogenous clearance test. However, a diagnosis suggested by an increase in plasma bile acid concentrations should be confirmed by standard liver function tests. In a similar manner, abnormal standard liver function tests can be confirmed as indicative of hepatic dysfunction by concomitant measurement of plasma bile acids. Plasma bile acid measurements may also be used serially to monitor patients with suspected or proven hepatic disease. However, they add little to standard tests of hver function and are now rarely used in clinical medicine. 

Figure 11.4 The inhibitory effect of E-sul on the E-sul. (b) Saturable uptake of telmisartan into hepatic uptake of pitavastatin (a) and E217fSG human hepatocytes was determined after the and telmisartan (b) [32,42], (a) The transport of subtraction of nonsaturable uptake (evaluated as pitavastatin (0.1 microM) into human the uptake clearance of 40microM telmisartan)...

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