Pharmacokinetic administration, distribution

Furthermore, pharmacokinetic administration, distribution, metabolism and excretion (ADME) factors affect drug bioavailability, efficacy and safety, and, thus, are a vital consideration in the selection process of oral drug candidates in development pipelines. Since solubility, permeability, and the fraction of dose absorbed are fundamental BCS parameters that affect ADME, these BCS parameters should prove useful in drug discovery and development. In particular, the classification can used to make the development process more efficient.For example, in the case of a drug placed in BCS Class II where dissolution is the rate-limiting step to absorption, formulation principles such as polymorph selection, salt selection, complex formation, and particle size reduction (i.e., nanoparticles) could be applied earlier in development to improve bioavailability. 

Mechanism of Action A direct thrombin inhibitor that reversibly binds to thrombin-active sites. Inhibits thrombin-catalyzed or thrombin-induced reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII also inhibits protein C formation, and platelet aggregation. Therapeutic Effect Produces anticoagulation. Pharmacokinetics Following IV administration, distributed primarily in extracellular fluid. Protein binding 54%. Metabolized in the liver. Primarily excreted in the feces, presumably through biliary secretion. Half-life 39-51 min. 

Pharmacokinetics Plasma concentrations peak within 0.5 to 2.5 hr after ocular administration. Distributed into aqueous humor. Metabolized in liver. Primarily excreted in urine. Half-life 3 hr. 

Pharmacokinetics Following IV administration, distributed readily into ascitic fluid. 

Pharmacokinetics What the body does to the drug. The process of drug absorption from the site of administration, distribution to the target organ and other bodily compartments, metabolism or biotransformation (if necessary), and eventual elimination. 

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4 the general principles of pharmacodynamics in Chapter... 

Pharmacokinetics Administration can be by an intravenous, oral, or topical route. The efficacy of topical applications is doubtful. The drug distributes well throughout the body, including the cerebrospinal fluid. Acyclovir is partially metabolized to an inactive product. Excretion into the urine occurs both by glomerular filtration and tubular secretion. Acyclovir accumulates in patients with renal failure. 

A lower incidence of myelosuppression has been observed and reported during studies on Abraxane but other toxic effects (sensory neuropathy, mucositis) are similar to those seen with Taxol given at high doses. Abraxane has been reported to produce keratopathy, which is a toxic effect rarely seen with drugs. Thus, as with the liposomal formulations described earlier (Section VIII.A.), the administration of nanoparticle based formnlations can dramatically alter the pharmacokinetics, the distribution of the drug in both tissnes and tumors, and the toxicity profile. Also, similar to what has been found with liposomes, the mechanism(s) by which nanoparticles release their drug payload is not well nnderstood as yet. 

Osaka, G., Carey, K., Cuthbertson, A., Godowski, P Patapoff, T., Ryan, A., Gadek, T., and Mordenti, J. (1996) Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice—use of a novel radionuclide approach. J. Pharm. Sci. 85(6), 612-618. 

Hustvedt SO, Grant D, Southon TE, et al. 1997. Plasma pharmacokinetics, tissue distribution, and excretion of MnDPDP in the rat and dog after intravenous administration. Acta Radiologica 38 690-699. 

Figure 41.6 Conceptual model of a druglike CORM. The number of CO ligands can be greater than 1 and the other ancillary ligands (L2-L6) can be the same or different. Distal substituents are just given as possible examples. ADME, administration, distribution, metabolism, and excretion PK, pharmacokinetics.

McMahon B.M., Mays D., Lipsky J., Stewart J.A., Fauq A., Richelson E. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev. 2002 12 65-70... 

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...

Usually, one has obtained an estimate for the elimination constant and the distribution volume Vp from a single intravenous injection. These pharmacokinetic parameters, together with the interval between administrations 0 and the single-dose D, then allow us to compute the steady-state peak and trough values. The criterion for an optimal dose regimen depends on the minimum therapeutic concentration (which must be exceeded by and on the maximum safe... 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

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. 

Piel et al. compared the intravenous pharmacokinetics of miconazole in sheep after its administration in a polyoxyl-35 castor oil/lactic acid mixture, a 100 pM hydroxylpropyl-/l-cyclodextrin-50 pM lactic acid solution, and a 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin 50 pM lactic acid solution. Intravenous administration of 4 mg/kg of miconazole was completed within 5 min [108]. There were no differences of the miconazole blood plasma concentration versus time for the three dosage forms. The half-life of distribution was <2.4 min. Both hydroxylpropyl-/ -... 

Ohzawa et al [112] studied the absorption, distribution, and excretion of 14C miconazole in rats after a single administration. After the intravenous administration of 14C miconazole at a dose of 10 mg/kg to the male rats, the plasma concentration of radioactivity declined biophysically with half-lives of 0.76 h (a phase) and 10.32 h (/ phase). After oral administration of 14C miconazole at a dose of 1, 3, or 10 mg/kg to male rats, the plasma concentration of radioactivity reached the maximum level within 1.25 h, after dosing and the decline of radioactivity after the maximum level was similar to that after intravenous administration. At a dose of 30 mg/kg, the pharmacokinetic profile of radioactivity in the plasma was different from that at the lower doses. In the female rats, the plasma concentration of radioactivity declined more slowly than that in male rats. The tests were conducted on pregnant rats, lactating rats, bile-duct cumulated male rats. Enterohepatic circulation was observed. In the in situ experiment, 14C miconazole injected was observed from the duodenum, jejunum, and/or ileum, but not from the stomach. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

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. 

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