Pharmacokinetics Blood-brain barrier

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...

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

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]. 

Poduslo JF, Curran GL, Gill JS. Pu-trescine-modified nerve growth factor bioactivity, plasma pharmacokinetics, blood-brain/nerve barrier permeability and nervous system biodistribution. 

HIV-protease. Examination of radiolabeled succinate 200 [202] provided information on the pharmacokinetic behavior of this water-soluble fullerene. A behavior similar to hydrophobic steroids was found, accompanied by a very low level of acute toxicity and the ability of 200 to penetrate the blood-brain barrier [162,195,199, 200, 203]. 

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 Crosses the blood-brain barrier. Extensively metabolized in the liver. Eliminated primarily by liver metabolism (not excreted renally). Haif-life 9-13 hr. 

Pharmacokinetics Poorly absorbed following PO administration. Does not cross the blood-brain barrier. Half-life Unknown. 

Pharmacokinetics Rapidly absorbed from the GI tract. Protein binding 84%. Crosses the blood-brain barrier. Undergoes extensive first-pass metabolism in the liver to active metabolite. Primarily excreted in urine. Half-life 14 hr. 

Pharmacokinetics Well absorbed from the GI tract and is unaffected by food. Does nof cross the blood-brain barrier. Protein binding greater than 98%. Primarily eliminated in feces. Half-life 1 2 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 Does not readily cross the blood-brain barrier. Metabolized in the liver. Excreted in the feces. Half-life 4 hours. Well absorbed with plasma concentrations proportional to the dose. 

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 About 30% absorbed. May be reduced with high-protein meal. Protein binding minimal. Crosses blood-brain barrier. Converted to dopamine. Eliminated primarily in urine and to a lesser amount in feces and expired air. Not removed by hemodialysis. Half-life 0.75 -1.5 hr. 

Pharmacokinetics Poorly and unreliably absorbed from the gastrointestinal (GI) tract. Limited ability to cross the blood-brain barrier. Primarily excreted in the urine and the bile. The effects of methscopolamine appear to occur within 1 brand last for 4-6 hr. Primarily excreted in urine. Half-life Unknown. 

Pharmacokinetics Penetrates blood-brain barrier. Rapidly hydrolyzed by cholinesterases. Small amount eliminated in urine largely destroyed in body by hydrolysis. Half-life Unknown. 

Pharmacokinetics Well absorbed after PO administration. Protein binding 14%. Crosses the blood-brain barrier. Metabolized by the liver to inactive metabolite. Eliminated primarily in urine and, to a lesser extent, in feces. Half-life 2-3 hr. 

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