Liver intrinsic clearance

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 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... 

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]. 

Fig. 10.12. (a) Experimental human liver microsome stability (FILM %Rem 1 . ) vs. calculated Log of solubility (c LogS). (b) Experimental human liver microsome stability expressed as apparent intrinsic clearance (FILM CL(int) xL/min/mg) vs. calculated Log of solubility (c LogS). A threshold value of cLogS > -3 and -4.0 is required for stability in FILM based on %R and intrinsic clearance, respectively. 

Obach, R. S., Kalgutkar, A. S., Soglia, J. R., and Zhao, S. X. (2008). Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from non-hepatotoxic drugs An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem. Res. Toxicol. 21 1814-1822. 

Figure 6 Well-stirred model of hepatic clearance. The exchange of a drug between plasma and hepatocyte and its removal from this cell involves an unbound compound. Intrinsic clearance, CLint, relates the rate of the elimination (by formation of metabolites, CLint>f, and secretion of unchanged compound into bile, CLint5ex) to the unbound drug in the cell, CUr Cbout and CUout are the bound and unbound concentrations of the drug leaving the liver at total concentration Cout.

Each term with a metabolic component (Fgm, Fh, CL) is a function of unbound fraction in blood (/ ) and intrinsic clearance (i.e., Emax/Km in biochemical terms) and can be modified by an enzyme/transporter inducer or inhibitor. If chug is completely absorbed and elimination occurs exclusively in the liver, the systemic AUC observed in the presence of a metabolic modulator would directly reflect... 

Note that the effect of the inhibitor in the liver is independent of blood flow. This is not the case for the intestine, where the relative magnitude of mucosal blood flow compared with the baseline mucosal intrinsic clearance and the apparent intrinsic clearance in the presence of inhibitor must be considered. When the baseline mucosal intestinal intrinsic clearance is negligible compared to mucosal blood flow (i.e., negligible mucosal extraction), Eq. (11) will collapse into a much simpler and better recognized equation for a hepatic inhibitory interaction (3). 

In turn the steady-state enzyme concentration in the liver determines the baseline hepatic intrinsic clearance, CLint, for the metabolism of a drug substrate by the enzyme. When substrate concentration, S, is low relative to the Michaelis constant, Km, for a particular biotransformation,... 

For a drug that is eliminated exclusively by the liver and that is completely absorbed following oral administration, the intrinsic clearance can be related to the area under the plasma concentration-time curve (AUCp0) if the well-stirred model of hepatic elimination is assumed (81,82) ... 

The O-deethylation of phenacetin is CYPlA2-mediated and results in the liberation of acetaldehyde that is subsequently metabolized to acetate and then CO2. Thus, a breath test based on the use of phenacetin labeled with 14C in the 1-position of the ethyl side chain could function to assess CYP1A2 activity. Early studies demonstrated the feasibility of this approach and its potential application to evaluating hepatic function (65,66). No extensive validation was attempted, so it is difficult to determine how well this test reflects the enzyme s intrinsic clearance, rather than perhaps some other determinant, such as liver blood flow. However, the situation appears to be moot since phenacetin is no longer an approved dmg worldwide because of its renal side effects following chronic dosing accordingly, further studies of this approach are unlikely. 

The extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

The binding to plasma or subcellular liver fraction can be taken into account for the prediction of human pharmacokinetic parameters either from preclinical and/or in vitro metabolism data (Obach et al. 1997 Mahmood 2000). Obach (1999) showed by comparison the in vivo investigated clearance values and clearance values projected from in vitro intrinsic clearance data of 29 drugs that the inclusion of blood and liver microsomes binding values gave the best agreement. 

However, in severe hepatic disease, not only is hepatic blood flow reduced but the degree of liver damage may influence intrinsic clearance to the extent that it also affects total drug clearance. Consequently, patients with hepatic disease are at particular risk of developing adverse effects to high extraction ratio drugs. 

Most opioids are metabolised in the liver and have a high intrinsic clearance/high first-pass effect. Therefore, when liver metabolism is impaired or when there is decreased blood flow through the liver (e.g. cirrhosis), clearance of opioids may be reduced, resulting in a prolonged duration of action and possible toxicity. Portal hypertension may also increase the oral bioavailability and hence the toxicity risk of opioids, as first-pass metabolism will be reduced. The probability of toxicity occurring is additionally dependent on a number of other patient and drug-related factors. 

The factors that affect hepatic clearance include blood flow to the liver (Q), the fraction of drug not bound to plasma proteins (fu), and intrinsic clearance (CGjjf) (1, 2). Intrinsic clearance is simply the hepatic clearance that would be observed in the absence of blood flow and protein binding restrictions. As discussed in Chapter 2, hepatic clearance usually can be considered to be a first-order process. In those cases, intrinsic clearance represents the ratio of Vmax l m, and this relationship has been used as the basis for correlating in vitro studies of drug metabolism with in vivo results (3). However, for phenytoin and several other drugs, the Michaelis-Menten equation is needed to characterize intrinsic clearance. 

---