High-clearance drugs

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. 

Cli and (Cli + Q) effectively cancel and Cl (or Cls) is equal to blood flow (Q). The implications of this on drugs cleared by metabolism is that the systemic clearance of low clearance drugs are sensitive to changes in metabolism rate whereas that of high clearance drugs are sensitive to changes in blood flow. 

The estimation of systemic clearance together with this value gives valuable information about the behaviour of a drug. High clearance drugs with values approaching hepatic blood flow will indicate hepatic extraction (metabolism) as a reason for low bioavailability. In contrast poor absorption will probably be the problem in low clearance drugs which show low bioavailabilities. 

Medication is readily decomposed in gastric fluid but may be stable in rectal fluid First-pass effect of high-clearance drug may be partially avoided... 

Beta-blockers can also affect the clearance of high clearance drugs by altering hepatic blood flow. This occurs when propranolol is co-administered with lido-caine (400), but it appears that this interaction is due more to inhibition of enzyme activity than to a reduction in hepatic blood flow (401). Atenolol inhibits the clearance of disopyramide, but the mechanism is unknown... 

First-pass effect of high-clearance drug may be partially avoided. 

Absorption from the rectum depends on various physiological factors such as surface area, blood supply, pH, fluid volume, and possible metabolism by microorganisms in the rectum. The rectum is perfused by the inferior and middle rectal arteries, whereas the superior, the middle, and the inferior rectal veins drain the rectum. The latter two are directly connected to the systemic circulation the superior rectal vein drains into the portal system. Drugs absorbed from the lower rectum are carried directly into the systemic circulation, whereas drugs absorbed from the upper rectum are subjected to hepatic first-pass effect. Therefore, a high-clearance drug should be more bioavailable after rectal than oral administration. The volume of fluid in the rectum, the pH of that fluid, and the presence of stool in the rectal vault may affect drug absorption. Because the fluid volume is... 

Daneshmend TK, Roberts CJC. The influence of food on the oral and intravenous pharmacc4c-inetics of a high clearance drug astudy with labetalol. BrJ Clin Pharmacol 9Z2) 14, 73-8. 

Equation (6.16) demonstrates that AUCoral is independent of Qi, and inversely proportional to CLint, h- This relationship is quite important in the screening of new drug candidates. However, it must be kept in mind that Eqs. (6.15) and (6.16) are derived using the well-stirred model. Thus, the prediction error may be significant for high-clearance drugs. 

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