Hepatic extraction

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... 

Table 1 Drugs Suspected to Have High Hepatic Extraction Ratios...

Biliary Excretion. The effects of significant hepatic extraction as a result of biliary secretion, with or without metabolism, would be expected to follow the same principles just outlined for hepatic metabolism. In fact, a whole class of compounds that serve as biliary contrast agents for radiological examination depend on significant first-pass biliary secretion to be effective. 

Metabolism J. Hepatic blood flow J. Liver size J. Phase I metabolism 1 Incidence liver dysfunction T t /2 hepatically extracted drugs... 

T. W. et al., Jejunal permeability and hepatic extraction of fluvastatin in humans, Clin. Pharmacol. Ther. 1996, 60, 493-503. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

T or si Free fraction of highly plasma protein-bound drugs si Clearance and T t1/2 for some oxidatively metabolized drugs si Clearance and T t1/2 for drugs with high hepatic extraction ratios si Clearance and T t 2 for renally eliminated drugs and active metabolites... 

The blood levels following oral and intravenous doses are very low in all animal species. This, most likely, is due to the marked affinity of the drug for various tissues and the rapid hepatic extraction of the absorbed fraction. The main route of excretion is the bile. Less than 5 % of the dose are recovered in the urine of intact animals after oral or intravenous administration. 

Lau, Y.Y. et al. 2002. The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios. Pharm. Res. 19 1606. 

With this experimental set-up, absolute bioavailability and hepatic extraction ratio ( h) can be directly calculated as per Eqs. 2.32 and 2.33 ... 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

The kinetics of disappearance from the circulation of intravenously administered human insulin (Fig. 6.32) is nonlinear [145]. Within a few minutes after injection, it becomes localized in the liver, heart, and kidneys, where it is rapidly metabolized. Indeed, the hepatic extraction could be as high as 70% on a single passage, whereas kidneys could account for 10-40% degradation. Enzymatic reduction of the disulfide bridges appears to be the first step in the in vivo metabolism of insulin, although this reaction appears of limited significance under in vitro conditions. 

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. 

Fig. 2.1 Schematic illustrating hepatic extraction with Q, blood flow and Cf intrinsic clearance (metabolism).

BioavailaMUty controlled by absorption and hepatic extraction (first pass effect)... 

The estimation of systemic clearance together with this value gives valuable information about the behaviour of a drug. High clearance drugs with values approaching hepatic blood flow will indicate hepatic extraction (metabolism) as a reason for low bioavailability. In contrast poor absorption will probably be the problem in low clearance drugs which show low bioavailabilities. 

All these compounds are moderately lipophilic and should show excellent ability to cross biological membranes by transcellular absorption. Propranolol, betaxolol and metoprolol all have minimal gut first-pass metabolism, as shown by the low value for E(g. i.). Metabolism and first pass effects for these compounds are largely confirmed to the liver as shown by the values for E(g. i.). In contrast talinolol shows high extraction by the gastrointestinal tract with low liver extraction [13]. These effects are illustrated graphically in Figure 3.9 which shows the bioavailability predicted from hepatic extraction contrasted with that seen in vivo in man. 

Fig. 3.9 Bioavailability (f) of propranolol (1), betaxolol (2), metoprolol (3) and talinolol (4) found in vivo in man compared to that predicted based solely on hepatic extraction.

Fig. 5.3 Structures of two combined TxSI/TxRAs subject to high hepatic extraction by sinusoidal transport systems.

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. 

Low hepatic extraction ratio and low protein binding to minimize reUance on hepatic blood flow. 

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