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Description: tiotropium bromide(136310-93-5) is a non-chiral quaternary ammonium compound that dissolves in water in small amounts. Tiotropium bromide was administered in dry powder inhalation. Most of the drugs deposited in the gastrointestinal tract, only a small amount of drugs to reach the target organ lung. Many of the pharmacokinetic data described below are obtained at higher doses than those recommended for treatment. 

Characteristics of the active ingredient

Absorption: The absolute bioavailability of 19.5% after inhalation of dry powder in young healthy volunteers suggests a high bioavailability to the lung. Based on the chemical structure of the drug (tetravalent ammonium compound) and the in vitro test results, it is speculated that tiotropium bromide(136310-93-5) is poorly absorbed in the gastrointestinal tract (10-15%). The absolute bioavailability of the oral solution of tiotropium bromide was only 2-3%. Tiotropium bromide reached its maximum plasma concentration 5 minutes after inhalation. Due to the nature of its tetravalent ammonium compound, the food does not affect its absorption. 

Distribution: The drug and plasma protein binding rate of 72%, the distribution volume of 32L /kg. At steady state, peak plasma concentrations of 17-19 pg /ml were measured 5 minutes after inhalation of 18 micrograms of dry powder in COPD patients, and then rapidly decreased in a multi-chamber model. The steady-state blood trough concentration is 3-4 pg /ml. The local concentration of the lung is unknown, but the mode of administration can be seen in the lungs of the actual drug concentration is higher. Studies in rats have shown that tiotropium bromide(136310-93-5) does not pass through the blood-brain barrier. 

Biotransformation: The extent of biotransformation is very small, as evidenced by the fact that 74% of the dose in the young healthy volunteers is excreted from the kidneys by the prototype. Tiotropium bromide is an ester that is not enzymatically resolved into alcohols (N-methyl scopolamine) and acids (dithienyl glycolic acid), both of which can not bind to muscarinic receptors. 

Experiments with human liver microsomes and human hepatocytes in vitro have shown that some drugs (less than 20% of the intravenous dose) are dependent on cytochrome P450 oxidation and subsequent binding to glutathione to various phase II metabolites. In vitro liver microsomal assays show that this enzymatic pathway is inhibited by CYP2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus, CYP2D6 and 3A4 are involved in metabolic pathways and are involved in the elimination of a small proportion of drugs. Tiotropium bromide(136310-93-5) did not inhibit cytochrome CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in liver microsomes even above the therapeutic concentration. 

Elimination: The terminal elimination half-life of tiotropium bromide(136310-93-5) is between 5 and 6 days after inhalation. The total clearance rate was 880ml /min in young healthy volunteers, and the variability among individuals was 22%. Intravenous administration of tiotropium was mainly excreted in the form of the original drug (74%). Inhalation of dry powder after 14% of the dose excreted by the urine, the remaining drugs are mainly in the intestine is not absorbed by the drug excrement by feces. Kidney clearance of tiotropium exceeded creatinine clearance, indicating that the drug was secreted into the urine. Patients with COPD had continuous inhalation once a day and achieved pharmacokinetic homeostasis after 2-3 weeks, with no further drug accumulation. 

Linear /non-linear: intravenous and dry powder inhalation after treatment within the therapeutic range, tiotropium bromide(136310-93-5) pharmacokinetics proved to be linear pharmacokinetics. 

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