Fraction of drug unbound

Fraction of dose reaching systemic circulation (bioavailability) Fraction of drug unbound Affinity constant... 

Usually the ratio of unbound plasma concentration (Cu) of the toxicant to total toxicant concentration in plasma (C) is the fraction of drug unbound, f , that is,... 

For lipophilic drugs, which are able to cross membranes and enter most of the tissue compartments (volume of the tissue compartment, Vt), the volume of distribution (Vd) can be calculated by knowing the volume of the plasma (Vp) and the fraction of drug unbound in the plasma ( / ) and in the tissue (juT) ... 

Q -H/c X ClitfT where Q is hepatic blood flow, fxj is the fraction of drug unbound in the circulation, and CZarr is intrinsic hepatic clearance. This parameter has been defined further to characterize the role of the individual processes of hepatobiliary transport and metabolism on clearance by the liver as follows ... 

It is also apparent that the efflux of drug from the tissue and retention in tissue is dependent on the fraction unbound in tissue and in the blood and on blood flow rate. Consequently, Roberts and Cross (1999) showed that the half-life of drugs retained in tissues (Igs = 0.693/ ,) could be related to the ratio of the fraction of drug unbound in the plasma and tissue (Figure 13.8). A number of other compart-mental and diffusion models have been described and summarized (McCarley and Bunge, 2001 Anissimov and Roberts, 2004). 

From this equation, we can see that the degree to which an increase in the fraction of drug unbound in the plasma will tend to increase a drug s apparent volume of distribution is dependent on the size of the ratio of the fraction of drug unbound in the plasma to the fraction unbound in the tissues ifupifut)- For the case of a drug with a small volume of distribution, this ratio is small. 

For the drug with a large volume of distribution, there is an almost proportional relationship between the fraction of drug unbound in the plasma and the apparent volume of distribution for the drug. 

Going back to Eq. 16.5, it can be seen that hepatic clearance is determined by three variables plasma flow to the liver, the fraction of drug unbound in the plasma and the intrinsic plasma clearance of unbound drug (Qh, fup and Cl inp respectively). The contribution of these variables to the value of hepatic clearance depends on the relative size of Qh compared with the product UpCl int. The numerical example in Table 16.4 shows the effect of changing p on hepatic clearance for a drug with /upCl mt > On (left side) and for a drug where upCl mt < On (right side). In this example plasma flow to the liver is considered to be constant at 0.8 mLmin . ... 

Table 16.4 The effect of changing the fraction of drug unbound in the plasma on hepatic clearance for two drugs, one where the term f pCI i , is greater than G i and one where it is lower than Qh...

Table 16.7 shows the effects of doubling the fraction of drug unbound in the plasma on the elimination half life of a dmg. These effects occur irrespective of whether an oral or an intravenous... 

This indicates that the half life is inversely proportional to hepatic clearance (which is unaffected by changes in tissue binding) and directly proportional to the apparent volume of distribution at steady state, which is inversely proportional to the fraction of drug unbound in tissues for drugs with large volumes of distribution. 

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