Hepatic extraction blood flow

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

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

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).

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. 

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

Flumazenil is a highly extracted drug. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In healthy volunteers, total clearance ranges from 0.7 to 1.3 L/h/kg, with less than 1% of the administered dose eliminated unchanged in urine. Elimination of drug is essentially complete within 72 hours, with 90% to 95% appearing in urine and 5% to 10% in feces. 

Lignocaine s clearance by the liver is flow dependent. In heart failure cardiac output may be very low and therefore hepatic blood flow through both the hepatic artery and the portal venous system is also low. This meant a lower extraction of the drug from the blood and accumulation of lignocaine until the high plasma concentration produced the central nervous system toxicity. 

Metabolism of drug during the first-pass through the liver may be reduced if its extraction depends on blood flow as hepatic blood flow is characteristically low in heart failure. This mechanism leads to a higher Cp of drugs in this group (e.g., lignocaine, an example discussed earlier in the chapter). 

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. 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not appear to do so.) May inhibit the renal tubular secretion of weak bases. Purportedly reduces hepatic blood flow, thus reducing first-pass metabolism of highly extracted drugs. (However, the ability of cimetidine to affect hepatic blood... 

Figure 7 Influence of changes in (a) organ blood flow on clearance, (b) fraction of the drug unbound in plasma (/u) on extraction ratio, and (c) intrinsic clearance on extraction ratio as predicted by the well-stirred model of hepatic clearance.

Note that the effect of the inhibitor in the liver is independent of blood flow. This is not the case for the intestine, where the relative magnitude of mucosal blood flow compared with the baseline mucosal intrinsic clearance and the apparent intrinsic clearance in the presence of inhibitor must be considered. When the baseline mucosal intestinal intrinsic clearance is negligible compared to mucosal blood flow (i.e., negligible mucosal extraction), Eq. (11) will collapse into a much simpler and better recognized equation for a hepatic inhibitory interaction (3). 

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 ... 

It has been demonstrated that hepatic extraction ratio (ER) is also influenced by blood flow. A number of mathematical models have been proposed to explain this observation, but the simplest model, and the one that is easiest to apply to clinical practice, is the well stirred or venous equilibrium model (Equation 5.3). This model relates hepatic clearance to hepatic blood flow (Q), the fraction of drug concentration that is unbound in plasma (fu) and the intrinsic clearance of the unbound drug (Clyint) [1]. Intrinsic clearance represents the maximum clearance of drug in the absence of any restrictions caused by blood flow, binding or access to the metabolising enzymes. The model states that ... 

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