Inhalation, administration pharmacokinetics

Schneider NG, Olmstead RE, Franzon MA, Lunell E (2001) The nicotine inhaler clinical pharmacokinetics and comparison with other nicotine treatments, Chn Pharmacokinet 40(9) 661-684 Schoedel KA, Sellers EM, Palmour R, Tyndale RF (2003) Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration. Mol Pharmacol 63(1) 96-104... 

To see how well Model 11 predicted an independent data set, pharmacokinetic data reported by Cone (1995) was used. Cone administered 22.2 mg cocaine intravenously over 10 s, 42 mg by inhalational administration, and 28.4 mg by intranasal administration to six male subjects. Exact details of how each inhaled cocaine... 

Rohatagi, S. Hochhaus, G. Mollmann, J. Barth, J. Galia, E. Erdmann, M. Sourgens, H. Derendorf, H. Pharmacokinetic and pharmacodynamic evaluation of triamcinolone acetonide after intravenous, oral, and inhaled administration. J.CUn.Pharmacol., 1995, 35, 1187-1193... 

H. Pharmacokinetic and pharmacodynsimic evaluation of triamcinolone acetonide after intravenous, oral, and inhaled administration. J.Clin.PharmacoL, 1995, 35, 1187-1193... 

Argenti D, Shah B, Heald D. A pharmacokinetic study to evaluate the absolute bioavaiiabiiity of triamcinolone acetonide following inhalation administration. J Clin Pharmacol 1999 39 695-702. 

Molhnan H, Wagner M, Meibohm B, Hocchaus G, Barth J, Stockman R, Kreig M, Weisser H, Falcoz C. Darendorf H. Pharmacokinetic and pharmacodynamic evaluation of fluticasone proprionate after inhaled administration. J Clin Pharmacol 1998 53 459 67. 

Inhaled tobramycin (TOBI ) is typically administered to patients 6 years of age and older in alternating 28-day cycles of 300 mg nebulized twice daily, followed by a 28-day washout or off period to minimize development of resistance. Longterm intermittent administration improves pulmonary function, decreases microbial burden, and reduces the need for hospitalization for IV therapy.24,25 Due to minimal systemic absorption, pharmacokinetic monitoring is not necessary with normal renal function. Lower doses of nebulized tobramycin solution for injection have been used in younger children, and studies are underway using 300 mg twice daily in children under age 6. 

The Mann et al. (1985) study is limited in that too few animals were used, organs other than the liver were not adequately evaluated, and only males were studied. Although an adequate acute-duration oral study would be useful to corroborate or refute the thyroid effects seen in the Mann et al. (1985) study, this does not represent a data need, since an acute oral MRL has been derived. Ingestion of contaminated drinking water is expected to be the predominant route of exposure for individuals living in the vicinity of hazardous waste sites. However, acute-duration inhalation and dermal studies in animals are needed to assess the potential toxicity of di- -octylphthalate following exposure via these routes because there are insufficient pharmacokinetic data available to support the extrapolation of data obtained after oral administration to other routes of exposure. 

Early IPL studies focused mostly on the metabolism of the bronchodilators and corticosteroids or the pharmacological activity of bronchodilators on the ex vivo preparation. Recently, the absorptive transfer of beclomethasone dipro-prionate (BDP) has been measured following administration to the human lung reperfusion model by two different commercially available inhalers for which human pharmacokinetic data are available for comparison [43],... 

Jendbro M, Johansson C-J, Strandberg P, Falk-Nilsson H, Edsbacker S (2001) Pharmacokinetics of budesonide and its major ester metabolite after inhalation and intravenous administration of budesonide in the rat. Drug Metab Dispos 29 769-776. 

Borlak J, Blickwede M, Hansen T, Koch W, Walles M, Levsen K (2005) Metabolism of verapamil in cultures of rat alveolar epithelial cells and pharmacokinetics after administration by intravenous and inhalation routes. Drug Metab Dispos 33(8) 1108-1114... 

Validation of the Model. The Corley model was validated using chloroform data sets from oral (Brown et al. 1974a) and intraperitoneal (Ilett et al. 1973) routes of administration and from human pharmacokinetic studies (Fry et al. 1972). Metabolic rate constants obtained from the gas-uptake experiments were validated by modeling the disposition of radiolabeled chloroform in mice and rats following inhalation of chloroform at much lower doses. For the oral data set, the model accurately predicted the total amounts of chloroform metabolized for both rats and mice. 

Interroute Extrapolation. The Corley model used three routes of administration, intraperitoneal, oral and inhalation, in rats and mice to describe the disposition of chloroform. This data was validated for humans by comparing the model output using the animal data with actual human data from human oral chloroform pharmacokinetic studies. Using the human pharmacokinetic constants from the in vitro studies conducted by Corley, the model made adequate predictions of the amount of chloroform metabolized and exhaled in both males and females. 

Costs are approximate (as of 2(X)2) and assume oral (gavage) administration and include costs of assay to confirm dose concentration and bioassay of pharmacokinetic samples. Significant variations for the same study design will be found between different contractors ( 20%), different study designs ( 25%) and different routes of administration (intravenous 25%, inhalation by snout only + 50-100%). 

Reproductive Toxicity. No studies were located regarding the reproductive effects of thorium in humans following exposure by any route. Neither inhalation nor oral reproduction studies in animals were located. Pharmacokinetic data following inhalation or oral exposure were not located to allow the prediction of possible reproductive effects. One dermal rat study found testicular effects after administration directly onto the scrotal skin. Additional inhalation, oral, and dermal reproduction studies and multigenerational studies would be helpful in assessing the potential risk to humans. 

Pharmacokinetics Minimal absorption after PO, inhalation, or nasal administration. Absorbed portion excreted in urine or by biliary system. Half-life 80-90 min,... 

Pharmacokinetics Phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15-20 minutes. After IM administration, a pressor effect occurs within 10-15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. The pharmacologic effects of phenylephrine are terminated at least partially bythe uptake of the drug into the tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified. 

Mechanism of Action A synthetic nucleoside that inhibits influenza virus RNA polymerase activity and interferes with expression of messenger RNA. Therapeutic Effect Inhibits viral protein synthesis and replication of viral RNA and DNA. Pharmacokinetics Rapidly absorbed from the GI tract following oral administration. A small amount is systemically absorbed following inhalation. Primarily excreted in urine. Half-life 298 hr (oral) 9.5 hr (inhalation). 

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

Perez-Reyes et al.8 estimated that only 32% of a dose of cocaine base placed in a pipe is actually inhaled by the smoker. Cone9 compared the pharmacokinetics and pharmacodynamics of cocaine by the intravenous, intranasal, and smoked routes of administration in the same subjects. Venous plasma cocaine concentrations peaked within 5 min by the intravenous and smoked routes. Estimated peak cocaine concentrations ranged from 98 to 349 ng/ml and 154 to 345 ng/ml after intravenous administration of 25-mg cocaine hydrochloride and 42-mg cocaine base by the smoked route, respectively. After dosing by the intranasal route (32 mg cocaine hydrochloride) estimated peak plasma cocaine concentrations ranged from 40 to 88 ng/ml after 0.39 to 0.85 h.9 In this study, the average bioavailability of cocaine was 70.1% by the smoked route and 93.7% by the intranasal route. Jenkins et al.10 described the correlation between pharmacological effects and plasma cocaine concentrations in seven volunteers after they had smoked 10 to 40 mg cocaine. The mean plasma... 

Various characteristics of the molecule influence its chances of reaching its target receptor since they influence the nature and extent of the body s effect on it. A drug s pharmacokinetic profile therefore determines the extent of the drug s opportunity to exert its pharmacodynamic effect. While there are various routes for human drug administration (oral rectal intravenous, subcutaneous, intramuscular, and intra-arterial injections topical and direct inhalation into the lungs), the most common for small-molecule drugs is oral administration, and discussions in the first part of this chapter therefore focus on oral administration. (In contrast, biopharmaceuticals are typically administered by injection, often directly into the bloodstream.)... 

Pharmacokinetics Epinephrine has a rapid onset but brief duration of action. In emergency situations epinephrine is given intravenously for the most rapid onset of action it may also be given subcutaneously, by endotracheal tube, by inhalation, or topically to the eye. Oral administration is ineffective, since epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only metabolites are excreted in the urine. 

Dix KJ, Coleman DP, Fossett JE et al. (2001) Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure. Xenobiotica 31 357-375 Mathews JM, Black SR, Burka LT (1998) Disposition of butanal oxime in rat following oral, intravenous and dermal administration. Xenobiotica 28 767-777 Okuyama Y, Momota K, Morino A (1997) Pharmacokinetics of Prulifloxacin. Arzneim Forsch/Drug Res 47 276-284 Simonsen L, Petersen MB, Benfeldt E, Serup J (2002) Development of an in vivo animal model for skin penetration in hairless rats assessed by mass balance. Skin Pharmacol Appl Skin Physiol 15 414 124... 

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