Clearance free drug

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 ... 

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

The lack of information conveyed by total brain concentration is indicated by studies on KA-672 [6], a lipophilic benzopyranone acetylcholinestrase inhibitor. The compound achieved total brain concentrations of 0.39 iM at a dose of 1 mg kg" equivalent to the IC50 determined in vitro (0.36 juM). Doses up to 10 mg kg were without pharmacological effect. Analysis of CSF indicated concentrations of the compound were below 0.01 juM readily explaining the lack of activity. These low concentrations are presumably due to high (unbound) free drug clearance and resultant low concentrations of free drug in the plasma (and CSF). 

Clearance of drug normally occurs from the liver and kidneys and it is an important assumption that only free (i. e. not protein bound) dmg is available for clearance. A diagram of the interaction of the major clearance processes is shown in Figure 5.1. 

Rather than looking at a metabolic pathway, similar models for the control of the mechanism of clearance by lipophilicity are demonstrated by considering drugs in general. Figure 5.7 illustrates free drug renal and metabolic clearance for a series of neutral compounds drawn from the literature [4]. 

Increased free fraction in plasma of some highly protein-bound acidic drugs. Free drug clearance of such drugs is better indicator of dose requirements than total clearance Small decreases in free fraction of basic drugs bound to ax-acid glycoprotein... 

In this example, the increased unbound phenytoin concentration resulted in a larger volume of distribution (more free drug distributed to the tissues), increased clearance (more free drug available for metabolism), but no change in the drug s half-life. The paradox in this case is that the increased clearance caused the total phenytoin blood concentration to go down, while the free concentration was elevated and led to clinical toxicity. Moreover, the unchanged half-life would not have clarified the cause of the subther-apeutic phenytoin level. 

After the drug is released from the particle (e.g., by dissolution, diffusion, or erosion), the three above listed mechanisms can also clear the free drug. Additional clearance of the released drug can take place as follows ... 

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