Drug in various tissues

Distribution, Localization, and Orientation of Drugs in Various Tissues and Membranes... 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

The blood levels following oral and intravenous doses are very low in all animal species. This, most likely, is due to the marked affinity of the drug for various tissues and the rapid hepatic extraction of the absorbed fraction. The main route of excretion is the bile. Less than 5 % of the dose are recovered in the urine of intact animals after oral or intravenous administration. 

In addition to phase I and phase II enzymes, equally important is a group of transporter proteins expressed in various tissues, such as the liver, intestine, brain and kidney, which modulate the absorption, distribution and excretion of many drugs. 

The study of ADME had its origins in pharmacology, the science of drugs. Because these processes involve rates of different types, this area of study came to be called pharmacokinetics The combined effects of these pharmacokinetic processes determine the concentration a particular chemical (the chemical entering the body or one or more of its metabolites) will achieve in various tissues and cells of the... 

Agents used to treat common fungal infections are listed in Tables 35-1 and 35-2. As indicated in Table 35-1, certain drugs can be administered systemic ally to treat infections in various tissues. Other agents are more toxic their use is limited to local or topical application for fungal infections in the skin and mucous membranes (Table 35-2). The use of systemic and topical antifungal agents is addressed in more detail below. 

The distribution of drugs depends on both the physicochemical properties of the drug molecules and the composition of tissue membranes. These factors can either result in a uniform or uneven distribution of dmgs into the various body compartments and fluids. In the extreme, distribution may tend toward an accumulation of drugs in particular tissues or to an almost complete exclusion of the drag from a particular compartment in a defined length of time. One unique compartment that has to be considered in this respect is the brain, which is separated from the capillary system of the blood by the blood-brain barrier, whose membrane has a special structure. It consists of a cerebral capillary network formed by a capillary endothelium that consists of a cell layer with continuous compact intercellular junctions. It has no pores, but special cells, astrocytes, which support the stability of the tissues, are situated at the bases of the endothelial membrane separating the brain and CSF from the blood. The astrocytes form an envelope around the capillaries. 

As already stated, the distribution pattern of dmgs in various tissues depends on both the structure and properties of the drug molecules and the composition of the membranes. 

Detailed in vivo studies on the tissue distribution in rabbits of a set of 10 drugs have been reported together with their partition coefficients, Kp, in various tissues and partition coefficients log Papp in four solvent systems octanol, benzene, chloroform, and triolein [91]. The results are summarized in Table 4.26. The Kp values in the studied tissues, including bones, showed a large variation in ranking and a significant variation from tissue to tissue. It was found that the tissue-to-plasma partition coefficient of the non-ionized form of the dmgs, Kf,(w correlates best with log Poet. of the non-ionized form. 

Also, according to Arnold et al. [390], the dose scheme of doxorubicin-loaded liposomes affects the drug accumulation in various tissues as well as the tumor. The authors reported that after repetitive doses of sterically stabilized liposomes (SSL)-DOX every week, the plasma half-life of the drug increased, the deposition in liver and spleen decreased, and peak concentrations of DOX in the heart were threefold... 

Chloroquine and hydroxychloroquine are quinoline drugs used for the chronic management of rheumatoid arthritis, discoid and systemic lupus erythematosus, and other collagen diseases. Because chloroquine is rapidly absorbed and becomes highly concentrated in various tissues due to melanin and protein binding, it is now used only for malaria prophylaxis. Hydroxychloroquine has replaced it primarily because of its superior safety profile. 

---