Oral administration, drug kinetics

Fletcher et al. [123] used a sensitive and specific gas chromatography-mass spectrometry method for the assay of primaquine in plasma and urine for studying the plasma kinetics. Preliminary studies on the effects of single and multiple oral doses were carried out. In both cases, the drug was completely removed from plasma in 24 h. The concentration of primaquine in plasma usually reached a peak 1-2 h after oral administration. The plasma elimination half-life was about 4 h. 

J. M. Irache, M. Berrabah, P. Verite, and S. Menager, Phenobarbitone-loaded poly-curly epsilon-caprolactone nanocapsules In vitro kinetics and in vivo behaviour by the oral route, in Formulation of Poorly-Available Drugs for Oral Administration, Paris, 1996, pp. 334-337. 

The kinetic properties of the various /3-blockers may be summarized as follows all of the so far available /3-blockers are readily absorbed after oral administration. Most drugs of this type are subject to hepatic degradation, usually leading to inactive metabolites. 

Prazosin is readily absorbed after oral administration, peak serum levels occur approximately 2 hours after a single oral dose, and the antihypertensive effect of prazosin persists for up to 10 hours. Its half-life in plasma ranges from 2.5 to 4 hours, and elimination from plasma appears to follow first-order kinetics. The drug is extensively (perhaps as high as 97%) bound to plasma proteins this observation partially explains the lack of correlation between plasma drug levels and persistence of antihypertensive effect. 

Zolpidem is rapidly absorbed and has a quick onset of hypnotic action. Bioavailability is 70 percent following oral administration and the drug demonstrates linear kinetics in the therapeutic dose range. Peak plasma concentration is reached at 0.5 and 3 hours. The elimination half-life is short. It is 92% plasma protein bound and is metabolised in liver to inactive metabolites. It is eliminated in the urine and in the faeces. 

For a typical drug with zero-order absorption, the concentrations after oral administration rise to a sharp peak and then quickly decline with no intermediate plateau. Examples of insoluble drugs whose absorption processes follow zero-order kinetics are cyclosporine (Grevel et al., 1986) and griseofulvin (Bates and Carrigan, 1975). 

Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with low doses of 10-20 mg/d and progressively increasing the dose until the desired effect is achieved. Less than 100 mg/d is usually sufficient to achieve adequate -receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below). 

Plasma pantoprazole concentrations decline monophasically after oral administration, with a mean plasma terminal half-life (tj P) of 0.9 to 1.9. Despite the short i r of pantoprazole, inhibition of acid secretion, once accomplished, is long lasting, persisting after the drug has been cleared from the circulation. Thus, the plasma kinetics of pantoprazole have little bearing on its antisecretory action [1],... 

The principles of physical and chemical laws are essential for the understanding of drug kinetics in mammalian species. This also applies to pharmacodynamics since the interaction of drug with the receptor(s) relies on the physicochemical principles of the law of mass action. In reality one can consider the entire course of drug in the body as consecutive and/or concurrent processes of diffusion and convection. For example, the oral administration of a drug may include, among many others, the following processes ... 

KINETICS OF DRUG ABSORPTION AFTER ORAL ADMINISTRATION... 

MPA usually reaches maximal concentrations within an hour of the time of oral administration of MME Distribution of the drug is rapid and essentially complete in most patients within 2 to 3 hours of administration. In whole blood, >99.9% of the drug is in the plasma compartment. MPAs clearance is affected by (1) glucuronidation, (2) enterohepatic circulation (EHC), and (3) the quantity of its free fraction. EHC is considered to be a significant contributor to the dose interval kinetics of MPA, especially the post-distribution phase of the concentration-time curve. The contribution of EHC to the MPA AUC is about 37%, ranging from 10% to 61%, based on the effect of concomitant administration of cholestyramine. The appearance of a secondary MPA concentration peak anywhere from 4 to 12 hours following the morning dose of MMF is believed to result from EHC. 

The AUCs can be obtained by administration of intravenous and oral formulations in a crossover study. It is important to use the exact dose rather than nominal doses the oral and intravenous formulations should be assayed, and the syringes or giving sets used for the intravenous administration carefully weighed before and after dosing. The size of the intravenous dose should be reduced compared with the oral dose in proportion to the expected bioavailability so that the AUCs will be similar. This avoids assumptions about linear kinetics and maximises safety, since high plasma concentrations by the intravenous route are avoided. Similarly, it is appropriate to infuse the intravenous drug over a period comparable with the time to maximum concentration (T j g ) after oral administration in order to avoid transient high peaks. 

Three common properties that affect intestinal absorption of drugs after oral administration are solubility, permeability, and p/f. Traditional solubility experiments measure solubility of solids placed into aqueous phases (thermodynamic solubility), but these methods are too slow or they consume too much material for drug discovery. Higher throughput methods must be used. The direct ultraviolet (UV) method [17] adds compound dissolved in dimethyl sulfoxide (DMSO) to an aqueous buffer and measures the UV absorption of the aqueous phase using a 96-well plate reader after equilibration and filtration (kinetic solubility). Lipinski has discussed the pitfalls that inadequate solubility information can have for a drug-discovery organization [18]. 

The kinetics of 5-fluorouracil and its metabolites are essentially nonlinear. Therefore it is extremely difficult to build models that would correctly describe the cascade of nonlinear transformations that are observed, starting from drug absorption to its transformation into the active moiety. More recently, capecit-abine has been commercialized. It is a fluor-pyrimidine carbamate available for oral administration. Concentrations of 5-fluorouracil in some tumors are higher than those in the adjacent healthy tissues. The tumor preferential activation of capecitabine to 5-fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phos-phorylase. It is interesting to note that the last of the three metabolic steps leading to 5-fluorouracil is the formation of 5 -deoxy-5-fluori-dine. Capecitabine is thus a pro-prodrug (176-178). 

This model can be used for additional situations—such as drug concentrations in the plasma following subcutaneous, intramuscular, or oral administration— if the kinetics of drug adsorption into the compartment are added. In this case, a mass balance on the central compartment (compartment 1) includes the slow absorption of drug ... 

Ldffler W, Landthaler R, de Vries JX, Waiter-Sack 1, Ittensohn A, Voss A, Zollner N. Interaction of allopurinol and hydrochlorotiiiazide during prolonged oral administration of both drugs in normal subjects. I. Uric acid kinetics. Clinlrtvestig 994) 72,1071-5. 

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