Blood-brain barrier , distribution pharmacokinetics

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

Octanol/water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [40, 41], blood-brain barrier (BBB) crossing [42, 43], and correlations to pharmacokinetic properties [1], In 1995 and 2000, specialized but very well attended meetings were held to discuss the role of log P in drug research [44, 45]. 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

Pharmacokinetics Rapidly absorbed. Protein binding 95%. Widely distributed throughout body tissues including erythrocytes, kidneys, and blood-brain barrier. Not metabolized. Excreted unchanged in urine. Removed by hemodialysis. Half-life 2.4-5.8 hr. 

Pharmacokinetics Well absorbed from the G1 tract (not affected by food). Protein binding less than 5%. Widely distributed. Crosses the blood-brain barrier. Primarily excreted unchanged in urine. Removed by hemodialysis. Half-life 5-7 hr (increased in impaired renal function and the elderly). 

Pharmacokinetics Rapidly and completely absorbed from the GI tract. Protein binding less than 36%. Widely distributed (crosses the blood-brain barrier). Primarily excreted unchanged in urine. Not removed by hemodialysis or peritoneal dialysis. Half-life II-I5 hr (intracellular), 2-11 hr (serum, adults), 1.7-2 hr (serum, children). (Increased in impaired renal function). 

Pharmacokinetics Well absorbed from theGl tract minimally absorbed after topical application. Protein binding less than 20%. Widely distributed crosses blood-brain barrier. Metabolized in the liver to active metabolite. Primarily excreted in urine partially eliminated in feces. Removed by hemodialysis. Half-life 8 hr (increased in alcoholic hepatic disease). 

Mecfianism of Action A nitroimidazole derivative that is converted to the active metabolite by reduction of cell extracts otTricfiomonas. The active metabolite causes DNA damage in pathogens. Therapeutic Effect Produces antiprotozoal effect. Pharmacokinetics Rapidly and completely absorbed. Protein binding 12%. Distributed in all bodytissues and fluids crosses blood-brain barrier. Significantly metabolized. Primarily excreted in urine partially eliminated in feces. Half-life 12-14 hr. 

The next major consideration during optimization for the pharmacokinetic/pharmaceutical phase concerns the design of drugs to overcome barriers during their distribution. Of these barriers, the blood-brain barrier is by far the most important to the drug designer. 

Pharmacokinetics (i.e. study of the movements of a medication) antipsychotics and other medications show differences in absorption, distribution, metabolism and excretion as a result of their different chemical structures and pharmaceutical preparations (capsule, tablet, injectable) and in relation to the conditions within the body (see Chapter 5). The transfer of a medication from the blood into the brain tissue across the so-called blood brain barrier, its binding to specific brain structures and thus its actions depend on the physicochemical properties of the molecule. The interplay of these and other factors explains why antipsychotics of different chemical structures are not equally effective milligram for milligram (Table 1.2 column 3) and why they differ with regard to onset and duration of action. 

Pharmacokinetics Both drugs are well absorbed orally. Amantadine distributes throughout the body and readily penetrates into the central nervous system (CNS), whereas rimantadine does not cross the blood-brain barrier to the same extent. Amantadine is not extensively metabolized. It is excreted into the urine and may accumulate to toxic levels in patients with renal failure. On the other hand, rimantadine is extensively metabolized by the liver. Metabolites and parent drug are eliminated by the kidney. 

The toxicity to the nervous system depends on the delivered dose and exposiue duration. In the case of pregnant women, pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern PAH disposition within the mother and the nervous system of children. Moreover, unique physiological features, such as the presence of a placental barrier and the gradual development of the blood-brain barrier influence PAH disposition and thus modulate developmental neurotoxicity. Because CNS effects are dependent upon windows of susceptibility when the lowest dose and shortest duration of exposure to environmental PAHs will have the greatest negative impact on brain development, a susceptibility exposure paradigm has proven to be the most reliable model in which to study developmental insult. The intent of this chapter was to review... 

EXHIBIT A Anatomical and Physiological Considerations Unique to Children. differences in anatomy. allometric scaling factors (e.g. increased surface area-to-volume ratio) cardiovascular status permeability of the pediatric blood-brain barrier (BBB). dermatologic factors (e.g. increased cutaneous blood flow) (Fluhr et al., 2000 Simonen et al, 1997). increased skin pH (Fluhr et al., 2004 Behrendt and Green, 1958) plasma protein binding volume of distribution (V ) organ size and maturity pharmacokinetic maturity (e.g. metabolic differences) (Fairley and Rasmussen, 1983)... 

The inherent difficulties in antagonizing a blocker Hke cocaine have led to the development of a pharmacokinetic approach that aims at acting directly on the drug itself to alter its distribution or accelerate its clearance [7-14]. Pharmacokinetic antagonism of cocaine could be implemented by administration of a molecule, such as an anti-cocaine antibody, that binds tightly to cocaine so as to prevent it from crossing the blood-brain barrier [ 15-20]. 

Gadolinium chelates for MRI (SEDA 18, 446) (SEDA-20, 419) (SEDA-21, 475) (SEDA-22, 503) are inert, non-metabolized, small molecules, with essentially the same pharmacokinetic properties as the iodinated contrast agents. They are rapidly distributed in the extracellular fluid spaces, both intravascular and extravascular, although they do not cross the normal blood-brain barrier, and are almost entirely excreted by glomerular filtration, with no significant active tubular excretion or re-absorption. Hepatic excretion occurs in patients with... 

Pharmacokinetic Rapidly, completely absorbed from GI tract. PB 25%-38% metabolized in liver widely distributed crosses blood-brain barrier, cerebrospinal fluid primarily excreted in urine minimal removal by hemodialysis. 

---