Distribution, drug with elimination

Some idea of the rate of absorption can be obtained from examination of the plasma concentration-time profile. It should be remembered, however, that the time to maximum plasma concentration Y ) is not when absorption is complete but when the rates of drug absorption and elimination are equal. Thus two drugs with the same absorption rate will differ in /max if elimination rates differ. Assessment of the rate of absorption can also be confounded by complex or slow drug distribution. For example, the calcium-channel blocker amlodipine has a much later /max than other similar drugs. This is not due to slow absorption but to partitioning in the liver membrane with slow redistribution. A quantitative assessment of the rate of absorption can be obtained by deconvolution of plasma profiles following IV and oral administration. 

The distribution and excretion of tritiated vincristine were studied by Castle and colleagues in rats and dogs (36). These investigators found that the drug was eliminated from the blood of both species in a biexponential manner, with half-lives of approximately 15 and 75 min. The persistence of low levels of radioactivity in the blood at late sampling times suggested that a third, very slow elimination phase contributes to the pharmacoki-... 

Figure 13.1. Compartmental model based on clearance and volume (Section 13.2.4.1). The drug is administered at a rate Ri into the central compartment, which is characterized by a volume of distribution K. The drug is transported to and from the peripheral compartment with inter-compartmental clearance CL12 and CL21, respectively (usually it is assumed that there is no net transport between the two compartments if the concentrations in both compartments are equal in this case CL21 = CLi2)- The peripheral compartment is characterized by a volume of distribution 1 2-Elimination may take place from both compartments and is characterized by clearance CL o and CL20, respectively.

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Diethylcarbamazine is an anthelmintic drug that does not resemble other antiparasitic compounds although it has some relationship with piperazine derivatives and it has been useful in the management of filariasis due to Wuchereria bancrofti or Brugia malayi and Loa loa and of tropical eosinophilia. It is a lipoxygenase inhibitor and alters the surface structure of the parasite making it more susceptible to destruction by the host. It is well absorbed and widely distributed. It is eliminated with an half-life of 5-13 hours both by metabolism and excretion unchanged in the urine. 

Acamprosate is administered as 1-2 enteric-coated 333-mg tablets three times per day. It is poorly absorbed, and food reduces its absorption even further. Acamprosate is widely distributed and is eliminated renally. It does not appear to participate in drug-drug interactions. The most common adverse effects are gastrointestinal (nausea, vomiting, diarrhea) and rash. It should not be used in patients with severe renal impairment. 

Pharmacokinetics is the study of the way that the body deals with pharmacologic compounds. In other words, what does the body do to the drug This includes the manner in which the drug is administered, absorbed, distributed, and eventually eliminated from the body. These topics are discussed in this chapter and the next. 

The central compartment represents the blood/plasma and any other tissue that rapidly equilibrates, relative to the distribution rate, with the blood/plasma (e.g., liver or heart tissue). The tissue compartment represents all other tissues that keep the drug and reach steady-state concentrations more slowly than the tissues of the central compartment. Since the two-compartment model is fairly robust in describing a bulk of all drugs, we will limit our discussion to two compartments with elimination... 

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