Clearance organ

Consider the situation outlined in Fig. 4.3. Following the administration of a drug, there is 

The ratio of the rate of elimination to the rate at which drug enters an organ is a dimensionless term that is called the extraction ratio ( ). 

Ca X Q = the rate at which drug enters the organ( igmin ) 

Based on steady-state and mass-balance considerations, the instantaneous rate of organ elimination is equal to the difference between the rate at which drug enters an organ and the rate at which it leaves an organ. This is equal to the product of the blood flow rate (Q) and the arterial-venous concentration difference (Ca - Cy). 

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However, for many drugs, blood flow is significantly greater than the intrinsic organ clearance (Q fu CLint) and then Eq. (5) reduces to... 

Organ clearances are usually based on in vivo rather than in vitro studies. Drug metabolic parameters, Vm and Km, can be estimated from in vitro hepatic enzyme and hepatocyte preparations [53], Knowledge of total clearance and fractional... 

CLi = organ clearance fi = fraction of dose eliminated by organ i CL = total systemic clearance... 

Blood drug concentration and amount of drug in urine versus time data are usually sufficient to obtain parameters for Eq. (65). No doubt for many drugs this information is available in the literature, and independent studies may be unnecessary. Intrinsic organ clearance, CL, as presented in Eq. (26), is obtained from... 

The major metabolic pathway for cisatracurium is Hofmann elimination, although renal and other organ clearance accounts for some elimination. The pharmacokinetics of cisatracurium are independent of dose in healthy adult patients up to doses of 0.2 mg-kg-1 and its elimination half-life is similar to that of atracurium (Table 6.4). In contrast to atracurium, the clearance of cisatracurium is slightly reduced and recoveiy slightly slower in patients with renal failure. Much less laudanosine is produced as a metabolite of cisatracurium as compared with atracurium even when the drug is given by continuous infusion over a prolonged period of time. 

The influences of plasma binding on drug elimination may be best understood by consideration of clearance. All organ clearance models incorporate a proteinbinding term. For example the conversion of the intrin-... 

By relating the rate of elimination to the entering concentration [Eq. (4)], an expression for organ clearance of drug can be obtained... 

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... 

The simple venous equilibrium model of organ clearance developed by Rowland and Wilkinson can be used to predict the effect of protein binding on hepatic plasma clearance ... 

Cisatracurium and atracurium share the same metabolic pathways, but Hofmann elimination may have a greater role in the elimination of cisatracurium than in atracurium (2,4-7). Spontaneous in vivo degradation accounts for 77 % of total body clearance of cisatracurium (6). Organ clearance is 23% of total body clearance. Major metabolites of cisatracurium are laudanosine and a monoquaternary acrylate. 

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. 

The total organ clearance (e.g., liver) will depend upon the intrinsic clearance (e.g., metabolic clearance) and the unbound fraction of the drug, fy. 

For many drugs, this information is available in the literamre, and independent studies may be unnecessary. Intrinsic organ clearance, Cl-, as presented in Equation... 

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