Drug absorption, pharmacokinetic administration routes

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 group of Byron and co-workers established an IPL model specifically to study drug deposition and absorption [14], and reported a novel technique for drug administration [15] and described the absorption of a variety of test compounds. The studies conducted in this model have been reviewed recently, along with a pharmacokinetic model developed to describe the disposition of the drugs administered via this route [119],... 

There is no doubt that the nasal route of administration of peptide and protein drugs is one of the most attractive alternatives to injections because of its convenience, which should assure good compliance by patients. The pharmacokinetic profile of peptide and protein drugs after nasal administration shows the occurrence of quick absorption and can be tailored, in some cases, by formulation approaches. This also may have therapeutic advantages. 

For all routes of administration, the absorption, distribution, and elimination kinetics are important for obtaining the desired therapeutic effect. For drugs expected to act in the eye after ocular absorption, pharmacokinetic parameters are difficult to obtain in both animals and humans. Accordingly, it has been proposed to rely essentially on pharmacodynamic measurements by use of a specific biological response after topical administration (258,259). For example, the apparent absorp-... 

The last simulation will be to simulate the pharmacokinetics given by a different route of administration. For instance, suppose a central venous line could not be established in an elderly 50 kg female patient, which is not that uncommon an occurrence. A physician then asks whether they could give the dose by intramuscular injection and whether this would impact the drug s pharmacokinetics. To simulate the pharmacokinetics after intramuscular administration requires an absorption model, which is unknown. Some guesses can be made, however, after a review of the published literature. 

We remain cognizant that this edition of the textbook includes some references that may be considered by some viewers not to be the most current. We, however, believe that the chosen references are classic ones best suited to illustrate a particular point. Additionally, we fully recognize that this edition omits topics such as the Wagner and Nelson method for the determination of the absorption rate constant, urinary data analysis following the administration of a drug by an extravascular route, two-compartment model pharmacokinetics for an extravascularly administered dmg, and metabolite kinetics. 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

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