Clearance intrinsic free

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

CIh Cl mt, the intrinsic free (unbound) clearance of drug (see below). 

Intrinsic free (unbound) clearance (Cl int) is the intrinsic clearance a drug would have in the absence of plasma protein binding. It is defined as ... 

Finally, we have the requisite equations to construct tables of expected outcomes of drug interactions from changes in intrinsic free clearance or in hepatic blood flow (Table 16.1 and Table 16.2.)... 

Table 16.1 Consequencesof a decrease in intrinsic free clearance (CI i t)°on parameters and pharmacological effect of a drug currently being administered...

Find the value of the intrinsic free clearance (Cl int). Will this be the same before and after the interaction ... 

Cl or Cls systemic clearance of a drug CIh hepatic clearance of a drug Clint intrinsic clearance of a drug Cl int intrinsic free (unbound) clearance of a drug... 

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 ... 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

Increased free fraction will cause an increased clearance of MPA, resulting in lower total MPA concentrations that return to baseline values when the condition that caused the change in free fraction becomes normal.In chronic renal failure, however, the total MPA concentration is often within the guidelines for effective immunosuppression, but the free concentrations can be substantially elevated—placing the patient at increased risk for overimmunosuppression. It is hypothesized that chronic uremia causes reduction in the intrinsic clearance that results in zero order kinetics for MPA clearance. 

Conversely, the opposite is observed for a compound with a low extraction ratio. The ability of the eliminating organ to remove drug depends on plasma binding and intrinsic organ clearance (CZ /x x Cli n) Such compounds are referred to as restrictively cleared and elimination is dependent upon the free fraction of the drug in the blood. 

Warfarin enantiomers are extensively metabolized by liver, possess a low hepatic extraction ratio, and are extensively bound (> 99%) to plasma proteins (Table 3). Therefore any change in the protein binding of warfarin enantiomers may alter the clearance and plasma concentrations of R- and S-warfarin [54]. Yacobi and Levy [54] studied the plasma protein binding of racemic and individual enantiomers of warfarin in human blood. The free fraction of R-warfarin was significantly (32%) larger than that of S-warfarin (Table 3). The authors concluded that the difference in the potency of warfarin enantiomers could not be solely explained by the observed differences in the protein binding of the individual enantiomers but rather by the intrinsic ability of R- and S-warfarin for interactions with extravascular receptors. 

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