Intrinsic clearance unbound

G. 75 drugs with log human intrinsic clearance unbound drugs [132]... 

Under this circumstance, the first-pass bioavailability is inversely proportional to the unbound fraction, and changes in the binding are expected to have a significant effect. It is also clear that changes in both the blood flow and the intrinsic clearance of the first-pass organ may have a significant effect when the extraction ratio is high (fu CL n Q). On the other hand, if... 

High-clearance drugs are those for which there is no saturation of the reaction that converts the drug, and therefore, the clearance rate approaches the blood-flow rate. For capacity-limited drugs, flow rate is irrelevant, and clearance is a simple product of the unbound fraction and the intrinsic clearance. 

Where Cl = Clg if only one organ is involved in drug clearance. Within this equation Cli is the intrinsic clearance based on total drug concentrations and therefore includes drug bound to protein. Lipophilic drugs bind to the constituents of plasma (principally albumin) and in some cases to erythrocytes. It is a major assumption, supported by a considerable amount of experimental data, that only the unbound (free) drug can be cleared. The intrinsic clearance (C ) can be further defined as ... 

It is important to recognize the distinction between the various terms used for drug clearance and the inter-relationship between these. Essentially intrinsic clearance values are independent of flow through the organ of clearance, whilst unbound clearance terms are independent of binding. These relationships are illustrated in Figure 2.2. 

Fig. 7.14 Unbound intrinsic clearance of CYP3A4 substrates and relationship with lipophilic-ity. The data has been calculated from various clinical studies with the drugs listed in order of decreasing lipophilicity. 

As observed in Figure 9.4 the intrinsic clearance (as represented by oral unbound clearance CIqu) of UK-147,535 shows an allometric relationship between the rat, dog and man. This would indicate that the transporter protein involved is conserved across these species and has similar affinity. However, marked reduction in clearance in the rabbit suggests the absence, or marked alteration, of the responsible protein in the hepatic sinusoidal membrane of this species. This finding may explain the common observation of reduced biliary excretion of acidic compounds in rabbits compared to other species [24, 25]. 

Figure 6 Well-stirred model of hepatic clearance. The exchange of a drug between plasma and hepatocyte and its removal from this cell involves an unbound compound. Intrinsic clearance, CLint, relates the rate of the elimination (by formation of metabolites, CLint>f, and secretion of unchanged compound into bile, CLint5ex) to the unbound drug in the cell, CUr Cbout and CUout are the bound and unbound concentrations of the drug leaving the liver at total concentration Cout.

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.

Each term with a metabolic component (Fgm, Fh, CL) is a function of unbound fraction in blood (/ ) and intrinsic clearance (i.e., Emax/Km in biochemical terms) and can be modified by an enzyme/transporter inducer or inhibitor. If chug is completely absorbed and elimination occurs exclusively in the liver, the systemic AUC observed in the presence of a metabolic modulator would directly reflect... 

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 ... 

Between these extremes, hepatic clearance is dependent on all three factors Unbound fraction of drug, intrinsic clearance, and hepatic blood flow. The unbound clearance, CLu, equals CL/A. 

Most pharmacokinetic theory has concentrated on explaining changes in clearance and bioavailability in terms of the parameters of intrinsic clearance, blood flow and fraction unbound [Eqs. (12) and (21)]. Yet the response of a patient to a dose or dosage regimen of a drug is dependent on the patient exposure to the drug, which is best characterized by AUC. Thus, it will be useful to consider the importance of individual parameters such as CLjnt, Q and / in terms of exposure concepts. Consider first an intravenous dose of a drug where from Eq. (7). 

Note that for oral dosing, exposure is inversely related to fraction unbound and intrinsic clearance... 

Variables in addition to liver blood flow that may influence the capacity of the liver to extract a drug from the blood for elimination by hepatic processes (biotransformation and/or biliary excretion of unchanged drug) are the unbound fraction in blood and the hepatic intrinsic clearance, which is a measure of the maximal ability of the liver to eliminate the drug. The hepatic clearance (with respect to blood concentrations) is determined by the following relationship between the variables which affect drug elimination by the liver ... 

Fig. 3.5 Allometric relationship between unbound antipyrine intrinsic clearance (C/U(int)) per maximum life-span potential (MLP) and body weight. Note that the body weight exponent of the regression equation is close to unity. Units on the ordinate (litres per MLP) are equivalent to C/U(int) (L/min) x MLP (min). (Reproduced with permission from Boxenbaum (1982).)...

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