Clearance intrinsic

Rat hepatocyte intrinsic clearance Human microsome intrinsic clearance Rat IV clearance... 

With this focus on CYP and fiver metabolism, most companies have established high throughput assays to measure compound stability in the presence of human (or preclinical species) fiver microsomes [49]. Disappearance of starting compound from an incubation with microsomes is monitored. Measurement at a single time point enables a rank-ordering of compounds for stability based on percent of parent compound remaining acquisition of data at multiple time points allows determination of half-life, intrinsic clearance, and extrapolation to a predicted in vivo clearance [50]. 

Fig. 3 Human liver microsome apparent intrinsic clearance (Clint,app) vs clogD. Open squares and filled triangles represent two different chemical series (series A and B, respectively)...

The intrinsic clearance of an organ is different from the value we normally think of as the clearance of the organ. The clearance of the organ is defined as the rate of loss in relation to the incoming concentration, whereas the intrinsic clearance is defined as the rate of loss in relation to the organ concentration (or exiting concentration). In addition, it is also clear that, of the... 

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... 

Q >fu CLint, then Eq. (7) simply says that the first-pass bioavailability is approximately 1 (i.e., little or no drug is eliminated in a first pass), and changes in binding, blood flow, and intrinsic clearance are not expected to have any effect on F. 

It is important to remember that absolute oral bioavailability is a function of both absorption and first-pass metabolism. Therefore, a linear approach to predicting absolute oral bioavailability based on a single parameter, such as rate or extent of absorption (fraction of dose absorbed or estimated dose absorbed) or the rate of metabolism (microsomal or hepatic intrinsic clearance), may result in an inaccu-... 

The age dependence of deltamethrin metabolism in vitro, and toxic signs and blood levels of the neurotoxic parent compound following administration of deltamethrin at 10 mg/kg p.o. was investigated [35]. Metabolism was quantified in vitro by monitoring the disappearance of the parent compound from plasma (via CESs) and liver microsomes (via CESs and CYPs) obtained from 10-, 21-, and 40-day-old male SD rats. Mean intrinsic clearances (Vmax/Km) in these respective... 

For competitive inhibition, the intrinsic clearance of a substrate by an inhibited enzyme can be described with the following equation ... 

Decrease in intestinal wail intrinsic clearance (CLinl Q)... 

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. 

Extraction is the ratio of the clearance process compared to the overall disappearance of the compound from the organ. The clearance process is termed intrinsic clearance Cli, the other component of disappearance is the blood flow (Q) from the organ. This is shown in Eigure 2.1 below. 

Fig. 2.1 Schematic illustrating hepatic extraction with Q, blood flow and Cf intrinsic clearance (metabolism).

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 ... 

Inspection of the above equation indicates for compounds with low intrinsic clearance compared to blood flow, Q and (Cl -i- Q) effectively cancel and Cl (or Cls) approximates to Cli. Conversely, when intrinsic clearance is high relative to blood flow. 

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. 

The predominant interaction of CYP3A4 is via hydrophobic forces and the overall lowering of lipophilicity can reduce metabolic lability to the enzyme. Figure 7.14 shows the relationship between unboimd intrinsic clearance in man and lipophilicity for a variety of CYP3A4 substrates. The substrates are cleared by a variety of metabolic routes including N-dealkylation, aromatization and aromatic and aliphatic hydroxylation. The trend for lower metabolic lability with lower lipophilicity is maintained regardless of structure or metabolic route. 

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. 

An alternative approach to relying simply upon allometric approaches for metaboli-cally-cleared compounds is to take into consideration their relative stability in vitro. Clearance by P450 enzymes observed in hepatic microsomes from different species provides a measure of the relative intrinsic clearance in different species. Using the equation for the well-stirred model ... 

The equation can be solved for intrinsic clearance (Clj) based upon systemic clearance (Clj) obtained after i.v. administration and hepatic blood flow (Q) in the test species. Intrinsic clearance in man can then be estimated based upon relative in vitro microsomal stabibty and the equation solved to provide an estimate for human systemic clearance. Hence this approach combines aUometry (by considering differences in organ blood flow) and species-specific differences in metabolic clearance. 

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]. 

Waller et al. (237) performed a CoMFA study to analyze the metabolic rates of CYP2E1 in rodents as intrinsic clearance of a 12 chlorinated volatile organic compounds (VOCs). After superimposition, the steric and electrostatic field interaction energies, the HINT (/jydropathic interactions) energy (238), and molecular orbital field were calculated in addition to clogP. The best model... 

The process is a bit more complicated for orally administered CYP3A-cleared compounds because a portion of the DDI can occur in the inteshne during the first pass. The principles described above are the same, except that (i) the value of/cL term for the intestine can essenhally be assumed as unity and (ii) the value of [I]j nvo for the perpetrator is higher than that used for liver. Importanhy, the extent to which the new compound is extracted by the intestine, which is a function of the intrinsic clearance (CLim) of the new compound by CYP3A4, plays a major role in the potential magnitude of the DDI. High CL t compounds can be subject to greater DDI [103]. 

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