Intrinsic metabolic clearance

For extrapolation of in vitro metabolism data to in vivo more detailed in vitro investigations are necessary as a first step. In this either enzyme kinetics is determined to calculate Km and Vmax and finally the intrinsic metabolic clearance as the quotient of both (Houston... 

FIGURE 30.12 Observed versus predicted intrinsic metabolic clearance of 29 drugs in humans. (Reproduced with permission from Ito K et al. Annu Rev Pharmacol Toxicol 1988 38 461-99.)... 

Wallace, K., and Dargan, J. (1987), Intrinsic metabolic clearance of parathion and paraoxmi by livers from fish and rodents. Toxicol Appl. Pharmacol. 90, 235-242. 

Enzyme induction or the process of creating excess enzyme in a biological system can give rise to pharmacokinetic situations whereby drug interactions occur. To fully understand the fundamental mechanism by which greater concentrations of enzyme can cause pharmacokinetic disequilibrium, we must describe the concept of intrinsic clearance. The maximum rate of metabolic clearance is the ratio of Vmax/ m referred to as intrinsic metabolic clearance (derived from M-M kinetics and assuming [substrate] < (Rowland, 1988). 

Determination of Hepatic Intrinsic Metabolic Clearance from in vitro Experimental Data... 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

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. 

In a first step the scaling of intrinsic clearances determined in rat hepatocytes was compared to in vivo clearance. When taking account of non-linearity, the estimated hepatic metabolic clearance values were in reasonable agreement with observed total clearances, which ranged from 7 to 35 mL/min/kg, and it was considered reasonable to estimate the expected clearances in human by a similar scaling of human hepatocyte data. The error around the mean predicted human clearance was based on the variability seen in different batches of human hepatocytes. 

Fig. 10.8. Cellular activity and hepatocyte stability of the 37 purified library compounds, (a) cLipE vs. human np-HSD1 EC50 (hHEKEC50). Chart enables rapid identification of the active and lipophilic efficient compounds (in lower right corner), e.g., PF-03440171 with cLipE = 8.7 and EC50 = 0.03 nM. (b) Fluman hepatocyte intrinsic apparent clearance (GLJiFlepCI) vs. hHEKEC50. Chart enables rapid identification of active and metabolically stable compounds, such as PF-03440142 with GLJiFlepCI = 5 pl/min/million and EC50 = 67 nM.

Riley RJ, McGinnity DF, Austin RP. 2005. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab Dispos 33 1304—1311. 

Third, the equations employed in a PBPK model should be consistent with the state of knowledge or biologically plausible hypotheses of the mechanisms of ADME for the particular chemical. In this regard, the uptake of chemicals in systemic circulation is described as either a diffusion-limited or perfusion-limited process (Gerlowski and Jain 1983), and metabolic clearance in individual tissues or tissue groups is described using a maximal velocity and Michaelis constant, intrinsic clearance, or hepatic extraction ratio (Krishnan and Andersen 2007). The mass balance differential equations accounting for uptake clearance, efflux clearance, and metabolic clearance are formulated as a function of identifiable input parameters (Table 21.1). 

Hepatic clearance can also be estimated from in vitro intrinsic metabolic CL obtained by incubation of a compound with hepatocytes or liver microsomes. This method requires fewer resources than the in vivo approach and is more suitable for screening a large number of compounds however, there are documented cases when in vitro clearance does not accurately predict in vivo. Intrinsic metabolic CL (CLint) is a parameter that only reflects the intrinsic ability of liver to metabolize... 

Oral clearance is a common term used in the pharmaceutical industry to describe the apparent CL of an orally dosed compound, expressed as CL// = Dose/AUC. Oral clearance is the reciprocal of dose-normalized AUC. Oral clearance reflects the overall exposure efficiency, without differentiating the efficiency of compound delivery or elimination, while IV clearance only reflects the exposure efficiency caused by elimination. Oral clearance is equal or higher than IV clearance. When bioavailability is high, oral clearance is very close to IV clearance. If the bioavailability is low, either due to low absorption or high first-pass effect, oral clearance can be much higher than IV clearance. High oral clearance indicates very low exposure efficiency. When absorption is complete (Fa% = 100), oral CL is actually the intrinsic hepatic clearance for a compound when hepatic metabolism is the major elimination route. Neither oral clearance nor intrinsic CL is limited by the blood flow. 

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 ... 

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. 

Indicator of intrinsic low-dose metabolic clearance rate... 

According to Mikata et al., the metabolism of bifenthrin, allethrin, resmethrin, P-cyfluthrin, cypermethrin, cw-permethrin, and /rans-permethrin was examined in rat and human hepatic microsomes (ScoUon et al. 2009). The intrinsic hepatic clearance of the pyrethroids was 5-15-fold greater to rat than to human nuCTosomes, except for /ranx-permethrin, which showed approximately 45 % greater clearance in human nuCTosomes. The metabolism of bifenthrin, allethrin and cix-permethrin in rat and in human hepatic nucrosomes was solely the result of oxidative processes. 

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]. 

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