Clearance excretion

It is also important to predict the in vivo biliary excretion clearance in humans, and for this purpose MDCK II cell lines expressing both uptake and efflux transporters may be used (Fig. 12.3) [92, 93]. It has been shown that MRP2 is expressed on the apical membrane, whereas OATP2 and 8 are expressed on the basolateral membrane after cDNA transfection (Fig. 12.3) [92, 93]. The transcellular transport across such double-transfected cells may correspond to the excretion of ligands from blood into bile across hepatocytes. Indeed, the vectorial transport from the basal to apical side was observed for pravastatin only in OATP2- and MRP2-expressing... 

Aoki, J., Suzuki, H., Sugiyama, Y., Quantitative prediction of in vivo biliary excretion clearance across the bile canalicular membrane from in vitro transport studies with isolated membrane vesicles. Abstract of Millennial World Congress of pharmaceutical Sciences, San Francisco, April 16-20, 2000, p. 92. 

Since CZtola is the sum of tissue uptake clearances and urinary excretion clearance, CLtotal is also expressed as ... 

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... 

Clearance. The volume of plasma that is cleared of drug per unit time by metabolism and excretion. Clearance is calculated additively The total clearance is the sum of clearance by the liver, the kidneys, and other routes. 

Figure 6 Directional transport of pravastatin in Oatplb2/Mrp2 double transfectants in the apical direction (A), and comparison of in vivo biliary excretion clearance and in vitro transcellular transport clearance across the double transfectant (B). (A) Transcellular transport across the monolayers of MDCK II cells was determined in the basal-to-apical and the opposite direction. (B) The x axis represents CLint determined in vitro multiplied by /B and the scaling factor, and the y axis represents the in vivo biliary clearance defined for the blood ligand concentrations. The symbol ( ) represents data whose x axis values were corrected for the scaling factor (a = 17.9). The solid line represents the theoretical curve, and the symbol (o), the observed data. Source From Ref. 59.

Excretion clearance from the plasma (urinary clearance) (liters/kg/day)... 

As shown in Section 10.5.1.2, clearance terms can be defined for specific types of elimination or for elimination in a particular organ or tissue. Thus the rate of excretion (r cr) is related to the excretion clearance... 

By a similar type of reasoning, it could be shown that the total clearance can also be written as the sum of metabolic and excretion clearances for each organ or tissue where metabolism or excretion of a drug takes place. Eor example, the overall clearance for a drug that undergoes hepatic metabolism as well as renal and bile excretion would become... 

The rale of elimination = Cl x Cp. Clearance is the sum of individual clearance values. Thus. C7p = C/ , (metabolic clearance) + C/, (renal excretion). Clearance, but not (, provides an indication of (he ability of the liver and kidney to di.spose of drugs. 

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