Oral drug administration pharmacokinetics

Buvanendran A, Kroin JS, Tuman KJ, et al. Cerebrospinal fluid and plasma pharmacokinetics of the cyclooxygenase 2 inhibitor rofecoxib in humans single and multiple oral drug administration. Anesth Analg 2005 100(5) 1320-1324, table of contents. 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

The standard pharmacokinetic parameters of the compound such as a half-life or bioavailability cannot be reliably calculated, because the concentrations in plasma are below lOpg/mL. As analogously expected from the results on the shift in keto-alcohol equilibrium of 16,16-difluoro-PGE2, it is rapidly metabolized by C-15 reduction mediated by the ubiquitously expressed carbonyl reductase. The metabolism followed by jS-oxidation and co-oxidation forms a mixture of a and fi epimers at the 15-hydroxy moiety as a sole measurable metabolite [46], In 2006, the US Food and Drug Administration approved the drug application for an oral treatment of chronic idiopathic constipation in adults, estimating that 4-5 million Americans are affected. Lubiprostone has also completed a phase II trial in constipation-predominant irritable bowel syndrome, and has been further evaluated for other bowel dysfunctions. 

Rectal bioavailability and pharmacokinetics. Serenoa repens extract, administered rectally to 12 healthy male volunteers at a dose of 640 mg/person, produced the mean maximum concentration in plasma of nearly 2.60 (Xg/mL approx 3 hours after administration, with mean value for the area under the curve AUC 10 (Xg/hour/mL. The bioavailability and pharmacokinetic profile were similar to those observed after oral administration. T j occurred approx 1 hour later, and plasma concentration 8 hours after drug administration was still quantified. The drug tolerability was good, and no adverse effect was observed ". Serenoa repens capsules, administered orally at a dose of 160 mg four times daily or rectally 640 mg daily for 30 days to 60 patients with BPH, produced no significant differences in diminu-... 

Chevalier, G., P. Benard, H. Cousse, and T. Bengone. Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon) supplemented with [l-14C]-lauric acid, [l-14C]-oleic acid or [4-14C]-beta-sitosterol. Eur J Drug Metab Pharmacokinet 1997 22(1) 73-83. 

Pharmacokinetic data on vernakalant are limited. After IV administration, the drug is metabolized in the liver by CYP2D6 with a half-life of 2 hours. However, on an oral regimen of 900 mg twice daily, sustained blood concentration was observed over a 12-hour interval. Clinical trials with the oral drug have used a twice-daily dosing regimen. 

The pharmacokinetic characteristics of florfenicol have been described in goats (40), calves (41), and chickens (42). The efficacy of florfenicol in aquaculture has been also demonstrated against bacteria involved in some major fish pathologies, especially in salmon and trout (43, 44). Pharmacokinetic studies in Atlantic salmon indicated that the compound was well absorbed and distributed following oral administration (45). Tissue residue depletion studies after an oral daily administration of 10 mg/kg bw florfenicol in rainbow ftout at 10 C for 10 days showed that muscle/skin tissue contained 150 ppb drug at 15 days after the last dose (46). 

Tauber, U., et al. 1986. Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone. Eur J Drug Metab Pharmacokinet 11 145. 

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.)... 

On the other hand, polycyclic aromatic compounds given orally or subcutaneously are more likely to cause aplastic anemia, leukemia, and lymphatic tumors in Ah-nonresponsive mice. These effects are manifest in tissues distant from the site of drug administration. In the example of oral benzo[a]pyrene, pharmacokinetic studies have shown a 10-and 20-fold higher uptake in the marrow and spleen of Ah-nonresponsive than of Ah-responsive mice this confirms the phenomenon called "first-pass elimination kinetics."... 

Considering that most novel therapies would rely on oral administration of drugs, such molecules have to fulfill requirements to achieve suitable pharmacokinetic behavior. The most quoted and commonly used guidelines are Lipinski s Rule-of-5 (8) and Veber s rotational bonds (9) that have been based on a statistical analysis of marketed oral drugs. Considering such boundaries, it has been estimated that about... 

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. 

Hoffman, A. Stepensky, D. Pharmacodynamic aspects of modes of drug administration for optimization of drug therapy. Crit. Rev. Ther. Drug Carrier Syst. 1999,16, 571-639. Stepensky, D. Friedman, M. Srour, W. Raz, I. Hoffman, A. Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation. J. Contr. Release. 2001, 71, 107-115. 

Figure 1.1 A schematic presentation of the fate of a drug in the body following oral administration. Pharmacokinetic processes are in blue, with the components of oral bioavailability in dark blue. Pharmacodynamic processes are in green, with the clinical effects in dark green.

Pairing these two particular antibacterial agents was based on pharmacokinetic factors and convenient availability. For such a combination to be useful in vivo, the two agents must arrive at the necessary tissue compartment where the infection Is at the correct time and in the correct ratio. In this context, the optimum ratio of these two agents in vitro Is 1 20. Of all the combinations tried, sulfamethoxazole came closest to being optimal for trimethoprim. Administration of a 1 5 combination of the two drugs orally produces the desired 1 20 ratio in the body once steady state is reached. Conveniently, sulfamethoxazole was already on the market, so it did not have to be approved specially by the U.S. Food and Drug Administration (FDA) for this purpose. 

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