Overall clearance

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

Excretion - Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The elimination half-life is about 1.4 hours. 

The virus reduction factor of an individual purification or removal—inactivation step is defined as the log10 of the ratio of the virus load in the pre-purification material divided by the virus load in the post-purification material. A clearance factor for each stage can be calculated and the overall clearance capacity of the production process assessed. Total virus reduction is calculated as the sum of individual log reduction factors. Individual manufacturing steps must possess fundamentally different mechanisms of virus removal or inactivation in order for values to be considered cumulative. Additionally, because viruses vary greatly with regard to inactivation or removal profiles, only data for the same model virus can be cumulative. 

The overall clearance of hemofiltration is more difficult to calculate than the diffusive clearance or the HF clearance, as it combines diffusive and convective transfers. An approximate equation for this clearance, obtained from an exact numerical solution has been given by Jaffrin et al. [12] as... 

The covariate analysis identified weight, sex, creatinine clearance, body mass index (BMI), and age as having an influence on PK parameters of NS2330 and/or Ml, respectively. The overall clearance of NS2330 is reduced by 20.5% in females compared to males and the NS2330 clearance which accounted for any elimination pathways except the formation of Ml from NS2330 (CLnon.met/F) is reduced in patients with a creatinine clearance lower than 62.5 ml/min ( 1.2% reduction per 1 ml/min reduction). The volume of distribution of NS2330 is influenced by body... 

The overall virus reduction capacity of a manufacturing process is the sum of the individual reduction factors, and should be greater than the potential virus load in the starting material. At least one step in the process should clear significant levels of infectious virus so that the overall clearance is not made up of individual small, and possibly negligible, reductions. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

The overall clearance (CL) has been defined in Section 10.5.1.2 as a parameter that relates the plasma... 

By a similar type of reasoning, it could be shown that the total clearance can also be written as the sum of metabolic and excretion clearances for each organ or tissue where metabolism or excretion of a drug takes place. Eor example, the overall clearance for a drug that undergoes hepatic metabolism as well as renal and bile excretion would become... 

Again, additional rate constants would be added to this sum as needed to account for the involvement of additional organs or tissues in drug elimination. Equations (10.70) and (10.75) can also be combined with the definition of the volume of distribution (T) in Equation (10.42) to give the relationship between the overall clearance (CL) and overall elimination rate constant k) as... 

It turns out that the fraction in this equation is related to the clearance associated with this elimination route CLj. te) relative to the overall clearance (CL), or the rate constant for this route (kroute) relative to the overall elimination rate constant (k), as given by... 

For one-compartment models, these equations yield essentially the same values of V and CL as those estimated from the linear regression analysis of In (Cp) versus t It will be seen later that for two-compartment models, however, these equations can provide a more universal estimate of overall clearance and an entirely different type of distribution volume. 

The terminal line analysis and the method of residuals analysis then provide values of k, ty eum, k, ty abst B. The model parameters that remain to be evaluated include the bioavailability F), the volume of distribution (V), and the overall clearance (CL). However, the information derived thus far from the data cannot be used to solve explicitly for any of these three variables. The best that can be accomplished at this stage is values for the apparent distribution... 

Adding the AUC contribution from each slice in Figure 10.52 then yields an estimate for the total AUC. The value of AUC can be related to the distribution volume (y) and the overall clearance (CL) by the general relationship... 

As in the method of residuals analysis, the bioavaU-ability F), distribution volume (V), and overall clearance (CL) cannot be independently solved, but can only be written as the apparent values... 

The AUC of a two-compartment model can be used to define a new type of distribution volume, and as usual provides an alternate means to determine the overall clearance. The value of ACC for the two-compartment bolus IV model can be calculated directly by the equation... 

The various distribution volume terms and overall clearance can be evaluated by... 

The remaining model parameters still to be determined include the overall clearance (CL) and the two-compartment distribution volumes (Fi, V s, Vauc)-As in the one-compartment first-order absorption model, these remaining model parameters cannot be calculated until the bioavailability (F) has been evaluated. This will require AUC calculations and a comparison to IV drug delivery results, as described in the next two sections. 

While these recent studies indicate the requirement for non-receptor-mediated steps in the overall clearance pathways for triacylglycerol-rich lipoproteins, the ultimate uptake occurs by endocytotic mechanisms involving specific receptors. Studies in a variety of experimental systems predicted that the removal of chylomicron remnants occurs independent of the LDL receptor, despite the presence of apo E on these particles. Accordingly, individuals with homozygous FH, who lack functional LDL receptors, show no signs of delayed clearance of chylomicron remnants. 

The total body clearance of a drug the from blood Is equal to the ratio of the overall elimination rate to drug concentration (Eq. 9.54), where the overall elimination rate Is comprised of the sum of the elimination processes occurring In all organs and the removal of a drug In all Its forms. Therefore, the overall clearance, (C/)g, represents the renal clearance (I.e., unchanged form of a drug) and the... 

FIGURE 5.2 Representative plot of how AUC changes in regard to/m x/m p45o and K, dissociation constant of inhibitor-enzyme complex [I], inhibitor concentration at the enzyme /m, fraction of dose metabolized via all CYPs /m,P4505 fraction of total CYP-mediated metabolism catalyzed by inhibited CYP form the product of/m x/m,p45o represents the contribution of a specific CYP enzyme to overall clearance. 

Abbreviations f, fraction of the dose metabolized by all CYPs , P45o, fraction of total CYP-dependent metabolism catalyzed by each CYP / xfnj 450, contribution of a specific CYP enzyme to overall clearance. 

Figure 5.2 describes in vitro reaction phenotype data for five CYP3A4 substrates that have gone into development. In each case, the impact of ketoconazole on their pharmacokinetics has been evaluated clinically. As expected, CYP3A4 played a major role in the overall clearance of compounds C, D, and E and ketoconazole elicited a marked impact on their pharmacokinetics (> 4-fold increase in AUQ. In comparison, the enzyme played a minor role in the clearance of compounds A and B and the AUC increase due to ketoconazole was less marked (< 2-fold). 

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