Hepatic extraction rate

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

An implication of the high degree of hepatic extraction is that clearance of nicotine should be dependent on liver blood flow. Thus, physiological events, such as meals, posture, exercise, or drugs perturbing hepatic blood flow, are predicted to affect the rate of nicotine metabolism. Meals consumed during a steady state infusion of nicotine result in a consistent decline in nicotine concentrations, the maximal effect seen 30-60 min after the end of a meal (Gries et al. 1996 Lee et al. 1989). Hepatic blood flow increases about 30% and nicotine clearance increases about 40% after a meal. 

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. 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

After the drug is absorbed, it may be taken up by hepatocytes and metabolized, a process that is referred to as the hepatic first-pass effect. If the compound is highly extractable, then the amount of drug removed is high and the degree of available drug is lowered. It is not known whether there are gender differences in hepatic blood flow that can influence the extraction rate of some medications. 

However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver s extraction of LDL precursors (VLDL remnants), thus reducing plasma LDL (Figure 35-2). Because of marked first-pass hepatic extraction, the major effect is on liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Limited reduction of LDL levels in patients who lack functional LDL receptors indicates that decreases in de novo cholesterologenesis also contribute to cholesterol reduction. Modest decreases in plasma triglycerides and small increases in HDL also occur. 

The extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

This means that overall exposure to unbound drug can t be affected by plasma binding or plasma protein binding displacement interactions. Furthermore, if the drug is a high hepatic extraction-ratio drug, such that CLint >Qj then Q hepatic blood flow rate, becomes limiting, and Equation (12.31) becomes ... 

The stereoselective pharmacokinetics of the selective serotonin reuptake inhibitor, citalopram, have been studied in 10 healthy young subjects [139]. After administration of 40 mg racemate daily for 21 days by the oral route, stereoselectivity was found in citalopram plasma concentrations. The R(—) S(+) ratios of Cmax and AUCss were 1.5 and 1.6, respectively. No difference was noted in suggesting similar absorption rates of the enantiomers. The terminal phase values were 47 and 35 h for the R and S enantiomers, respectively. Renal clearance comprised 20% of each enantiomer s total clearance and was nonstereoselective. Although both enantiomers are extensively metabolized, both possess low hepatic extraction ratios [139]. Serotonin reuptake inhibition of citalopram primarily resides with the S enantiomer (see Chap. 5, Sec. 3.4 for more details), which attains lower concentrations in plasma. In eight geriatric patients (mean 77 y) given... 

Pick s ffrst law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug... 

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