Pharmacokinetic Barriers

In the following sections tumour cell-directed targeting and intracellular delivery of drugs will be discussed. This includes crucial factors such as tumour structure and physiology as well as physiological, cellular, molecular, biochemical and pharmacokinetic barriers. 

Describe the pharmacodynamic and pharmacokinetic barriers to effective plasmid-based gene delivery. 

Pharmacokinetic barriers Low oral absorption Marked presystemic metabolism Short duration of action Unfavourable distribution in the body... 

Pharmaceutical barriers Insufficient chemical stability Poor solubility Inacceptable taste or odour Irritation or pain Pharmacokinetic barriers Insufficient oral absorption Marked presystemic metabolism Short duration of action Unfavorable distribution in the body Pharmacodynamic barriers Toxicity... 

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...

The simplest case of pharmacokinetics is intravenous injection [1]. In this case the drug is injected directly into the bloodstream. The drug may permeate to different tissues depending on its ability to get across the blood vessel walls and the cellular barriers in the particular tissue targets (Fig. 1). If the drug has small molecular weight and adequate... 

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. 

The amounts of ointments and creams people apply are highly individualized. So are the techniques of application. Some patients vigorously rub semisolid formulations into the skin, while others just spread films until they are more or less uniform over the desired area. While pharmacokinetic assessments of a system s delivery attributes is ordinarily done using normal skin (in vitro) or on healthy volunteers (in vivo), the site of its clinical deployment is usually anything but normal. Rather, it is determined by the skin condition to be treated. Clearly, the manufacturer is without control over how a disease is expressed in a particular patient. For many diseases, disease manifestation can be anywhere on the body. Moreover, from individual to individual it varies in intensity and vastness. Thus, more area may be involved in one case than in another, and the barrier function of the skin may be more or less intact in any instance. This creates a set of imponderables with respect to delivery, efficacy, and safety. 

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]. 

Zhang, Y., Benet, L. Z., The gut as a barrier to drug absorption combined role of cytochrome P450 3A and P-glycoprotein, Clin. Pharmacokinet. 

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

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