Donald C. Hobbs

Piroxicam Pharmacokinetics in Man: Aspirin and Antacid Interaction Studies

Pharmacokinetic studies with piroxicam, a nonsteroidal antiinflammatory agent, have been carried out following the administration of single and multiple oral doses. A plasma half-life of approximately 45 hours is observed, permitting the use of single daily doses in therapy. Enterohepatic recirculation of drug is suggested by the presence of multiple peaks in plasma concentration curves. Piroxicam is highly bound to serum proteins. The absorption and disposition of piroxicam are unaffected by the concomitant administration of aspirin and antiacids. Salicylate plasma levels are similarly unaffected by piroxicam administration.

Distribution and metabolism of doxepin

Abstract Drug metabolism studies with doxepin in rats and dogs reflect the fundamental similarity of its structure to that of the related tricyclic psychotherapeutic agents, amitriptyline and imipramine. Doxepin is well absorbed after oral administration and measurable amounts of doxepin and demethyl doxepin quickly appear in the blood. Although numerous metabolites of doxepin are observed in liver and in urine, only doxepin and demethyl doxepin are found in the rat brain, where the same ratio of cis - and trans -isomers as in the administered drug is still present. Metabolic transformations include demethylation, N -oxidation, hydroxylation and glucuronide formation. In the rat, doxepin and its metabolites are found in all tissues examined but, with the exception of the pigmented eye, are rapidly cleared. This affinity for melanin is also reflected in studies in vitro with beef eyeball melanin, where, however, doxepin is less strongly bound than is amitriptyline.

Pharmacokinetics of Prazosin in Man

Prazosin was administered orally to 24 normotensive human subjects in the form of capsules or as a solution. Plasma concentrations indicate that drug is almost completely bioavailable from the capsules, although levels peak more slowly than from drug in solution. Drug leaves plasma with a half-life of approximately 2.3 hours. Examination of data from each subject on repeated dosing indicates considerable intrasubject consistency in pharmacokinetic response despite intersubject variability. The absence of the pharmacologically active metabolites in plasma suggests that the hypotensive response derives from drug only. Prazosin is bound to human plasma proteins to the extent of 97%.

Interaction of sudoxicam and aspirin in animals and man.

In rats, both the plasma concentrations and the anti‐inflammatory activity of sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of sudoxicam are not affected by concurrent administration of aspirin. In this respect sudoxicam differs from such other nonsteroidal anti‐inflammatory agents as indomethacin and naproxen.

Chapter 20: Drug Metabolism

Publisher Summary This chapter illustrates distribution and metabolism of drugs in the lungs, the relationship of drug metabolism and disposition to safety, drug interactions, hepatic esterases and amidases, metabolic factors in liver toxicity, hemodynamic factors in drug disposition, and the blood–brain barrier. The fact that metabolic events frequently lead to active or toxic metabolites merits consideration by the medicinal chemist as does information on new or little studied biotransformation routes. Species differences in drug metabolism are also addressed because they bear directly on the relevance of efficacy and toxicity observed in animals to usefulness in man. Drug metabolism studies are of greatest value to the drug discovery process when they are carried out early and permit rapid feedback to the synthetic program. The frequency with which the toxicity of drugs and other chemicals is mediated by metabolism and covalent binding of a reactive species to tissue macromolecules has stimulated considerable study of the biotransformation of a number of new and important agents. Increasing evidences suggest that intermediate epoxide formation is an important metabolic transformation of xenobiotics that contain an aromatic or olefinic double bond. The recognition that metabolism may vary with the species employed is important for the extrapolation of animal data to man. The problems and considerations involved in the selection of appropriate species for toxicology and drug metabolism studies have been pointed in the chapter.

Pharmacokinetics of Benzquinamide in Man

Using a newly developed sensitive gas chromatograph-mass spectrometer assay for benzquinamide, pharmacokinetics have been determined in man follovnng the administration of intramuscular, oral, and rectal suppository doses. Drug is absorbed most rapidly from the intramuscular dose and least rapidly from suppositories. The mean apparent elimination half-life is 1.0–1.6 hr from all formulations. Benzquinamide is 33–39% bioavailable from the capsule and suppository formulations, relative to the intramuscular formulation. A high correlation between capsule and suppository bioavailabilities suggests that first-pass metabolism may account for at least part of the incomplete availability.