Pharmacokinetic and bioavailability studies

The determination of these compounds in biological fluids is crucial for several reasons such as investigating overdosing (toxicological monitoring), conducting pharmacokinetic and bioavailability studies, and measuring compliance. 

Radhofer-Welte and Dittrich [35] described a rapid and sensitive HPLC method for the determination of lornoxicam in plasma samples of humans and laboratory animals. After addition of the internal standard, tenoxicam, the plasma was acidified and extracted by dichloro-methane via Extrelut columns or by solid-phase extraction using Cis columns. After evaporation of fhe solvenf, fhe separation is performed on a Ci8 column in isocratic mode wifh a mobile phase consisting of 0.1 M phosphafe buffer (pH 6)-methanol, and defection at 372 nm. The limit of deferminafion was set to 10 ng/ml using 0.5 ml of sample but can be extended down to 2 ng/ml plasma. Using solid-phase extraction with Cis columns both lornoxicam and its main metabolite 5 -hydroxylornoxicam can be determined while extraction via Extrelut was used in studies where only lornoxicam was to be determined. The method was used in several thousand samples of pharmacokinetics and bioavailability studies in animals and humans. 

DENNIS J. RUNSER is director of chemical affairs for Marlon Laboratories, Inc., Kansas City, Mo. His responsibilities include analytical and bioanalytlcal research, stability testing, synthesis, pharmacokinetics, and bioavailability studies. He received his B.S. degree in chemistry from Illinois Benedictine College and his Ph.D. from the University of Iowa. He is also currently adjunct professor on the faculty of the University of Mlssouri-Kansas City. Dr. Runser is named in "Who s Who in the Midwest" and is a certified as a professional chemist by the American Institute of Chemists. He has held management positions in quality control and analytical research with G. D. Searle Company and the... 

Metabolism, pharmacokinetics, and bioavailability studies, initially on a preclinical level but later after human testing is approved, are also supported by LC analytical methods of drug and metabolite levels determination in various biological fluids and tissues. These studies and those to support further toxicology testing are the subject of other articles. 

Assay of Underivatized Nitrazepam and Clonazepam in Plasma by Capillary Gas Chromatography Applied to Pharmacokinetics and Bioavailability Studies in Humans... 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Animal studies Pharmacokinetics and bioavailability of aescin was studied after oral and i.v. administration of tritiated aescin (108,109). About 66% and 33% of the dose was excreted in bile and urine, respectively, after i.v. administration. The oral bioavailability of aescin was about 12.5%. Percutaneous absorption of aescin was studied in mice and rats (110). The amounts of aescin in muscle were greater than in other organs. These results indicate that percutaneous administration of aescin could be beneficial. 

Pharmacokinetic and bioavailability (absolute and relative) experiments are usually designed and conducted to evaluate dose proportionality over the dose range used, or expected to be used, in toxicology studies and possible species-to-species differences in pharmacokinetic profiles. With the incorporation of one or two I.V. dose levels into the study protocol, the drug candidate s absolute... 

Yuan, Y.-S. Shen, M. Study on pharmacokinetics and bioavailability of terbutaline by high-performance liquid chromatography with electrochemical detection. J. Chin. Pharm. Sci. 1994, 3, 152-156. 

Another study in six healthy volunteers studied the pharmacokinetics and bioavailability of anthocyanidin-3-glycosides from either blackcurrant juice or elderberries (24). As with other studies listed previously, these investigators found very little ( 0.04% from blackcurrant juice to 0.4% from elderberry extract) of the dose recovered in the urine, suggesting low bioavailability. Though the half-life of the anthocyanidins was similar regard-... 

Yeh, K.C., Stone, J.A., Carides, A.D., Rolan, P Woolf, E. and Ju, W.D. (1999) Simultaneous investigation of indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope labelling technique study design and model-independent data analysis. Journal of Pharmaceutical Sciences, 88, 568-573. 

Drug formulation Pharmacokinetics and bioavailability of parental diazepam were compared with two novel intranasal diazepam formulations (intranasal solution and intranasal suspension) in a randomised, open-label, pilot study in 24 healthy volxmteers [9 ]. Participants received two intranasal and one intravenous dose of diazepam with 2 weeks washout period between doses. Both intranasal formulations were well tolerated. Diazepam concentration... 

Lansoprazole, after oral administration, has a higher bioavailability and faster onset of antisecretory effect than omeprazole, although both agents have many similarities in structure and mechanisms of action [42, 55]. Results from pharmacokinetic and pharmacodynamic studies have shown that, after a single dose of lansoprazole, the absolute bioavailability was 81 % for the 15-mg and 85-91 % for the 30 mg doses, respectively [56,57], and these remained steady after repeated dosing [56]. This has been confirmed in a recent study in healthy volunteers in whom once-daily lansoprazole 30 mg was given for 4 days, and the maximum antisecretory effect was obtained 6 h after the first dose and remained consistent with subsequent dosing [58]. 

The route and frequency of administration should be as close as possible to that proposed for clinical use. Consideration should be given to pharmacokinetics and bioavailability of the product in the species being used, and the volume which can be safely and humanely administered to the test animals. For example, the frequency of administration in laboratory animals may be increased compared to the proposed schedule for the human clinical studies in order to compensate for faster clearance rates or low solubility of the active ingredient. In these cases, the level of exposure of the test emimal relative to the clinical exposure should be defined. Consideration should also be given to the effects of volume, concentration, formulation, and site of administration. The use of routes of administration other than those used clinically may be... 

Since 1999, when the Food and Drug Administration allowed the first health claim for soy-fortified foods in the USA, there has been a large increase in the sales of food products claiming to contain soy isoflavones. At the same time, over-the-counter supplements have become widely available. However, concerns have been raised about the real health benefits of such supplements in the absence of adequate information about bioavailability, pharmacokinetics and safety. To fill this gap, an extensive study on pure isoflavones and commercial soy isoflavone supplements has recently been carried out (Setchell et al, 2001). A selection of 31 commercially available supplements showed a wide variation in isoflavone composition and in the amount provided by one tablet. Furthermore, a lower isoflavone content, with respect to the claimed levels, has been observed in almost 50% of the analysed products. In one case, no isoflavones at all could be detected (Setchell et al, 2001). 

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

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