Pharmacokinetics significance

Koren G. Clinical pharmacokinetic significance of the renal tubular secretion of digoxin. Clin Pharmacokin 1987 13 334-343. 

Semisynthetic Derivatives. No significant improvements in activity have resulted from modifications of the 3-, 9-, 2and/01 4"-hydioxyl groups (314). 3 -0-Acyl derivatives have not been found via fermentation, but chemical acylation of the 3 -hydroxyl group yields products having good antibiotic activity and better pharmacokinetics than the patent macroHdes. Two such compounds have been developed (315,316) ... 

Dtug interactions can cause serious problems in clinical practice especially when the affected dmg has the potential to be highly toxic. Furthermore, pharmacokinetic interactions are clinically important if the affected dmg has a narrow therapeutic range (i.e. small difference between the minimum effective concentration and the toxic concentration Fig. 1) and a steep concentration-response curve (i.e. significant alterations in pharmacological and/or adverse effects caused by small changes in blood concentration). 

A pro-drug approach for improving the pharmacokinetics of zanamivir has recently shown some promise. The alkoxyalkyl ester 23 of zanamivir, with long alkyl chains chosen to counteract the high hydrophUicity of the molecule, was reported to show significant protective effects against influenza (HlNl) infection in mice upon oral or intraperitoneal administration (Liu et al. 2007). 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

There was a significant negative correlation between (log) admission urinary PCP level and self-reported time since last PCP use (r= -0.53, p<0.001). Visual inspection of a graph of these two variables suggested a possible biphasic elimination curve, with the initial phase having a half-life of 5 to 7 days, and the later phase a half-life of about 30 days. However, formal curve fitting of these data to standard pharmacokinetic models (using BMDP... 

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