Transporters overall hepatic uptake

Prediction of the Contribution of Each Transporter to the Overall Hepatic Uptake... 

Figure 11.3 Schematic diagram ofthe methods for estimating the contribution of each transporter to the overall hepatic uptake [250] (a) using reference compounds (b) using the relative expression levels estimated from Western blot analysis and (c) using transporter-specific inhibitors. The details are described in the Section 11.5.2.

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. 

Always a determinant of net hepatic clearance (regardless of other mechanisms involved). Changes in sinusoidal uptake (e.g., due to transport inhibition) will affect overall hepatic clearance, even for drugs that are highly metabolized. 

The findings of the present investigation indicate that the K , value for hepatic taurocholate uptake significantly increases at birth in the rabbit. This observed increase in K , indicates that the overall efficiency of hepatic uptake of taurocholate decreases at birth. Conceptually, this observed change in can be attributed to two factors (a) alterations in the hepatocyte membrane to affect carrier conformation and mobility (b) structural modifications in the carrier protein. Recent studies by Benz et al. (1977) on the influence of membrane structure on carrier-mediated transport demonstrated that the translocation rate constant or K,n is strongly dependent on the nature of the membrane structure. 

Metabolism in pediatric patients can be quite different from adults. In the very young infant, drug uptake by the liver is decreased due to reduced transport proteins. The biliary excretion of antibiotics with dual routes of elimination suggests that hepatic transport maturation is even slower than glomerular filtration or renal transport maturation. Overall, mixed function oxidases are present at 30-50% of adult activity, while individual enzymes may be less than 5% of adult activity. In particular, isoenzymes of CYP 2C9 and 1A2 have greatly reduced activity in neonates however, there is a rapid increase in 2C9 activity in the first weeks of life. After birth. Phase I and II enzymes have a programmed order of expression, which is different for each isoenzyme. Some isoenzymes increase in days, others over weeks, and stUI others over months. 

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