Ketoprofen dosing

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

Other arylpropionic acids include naproxen, ketopro-fen and flurbiprofen. They share most of the properties of ibuprofen. The daily oral dose of ketoprofen is 50-150 mg, 150-200 mg for flurbiprofen and 250-1000 mg for naproxen. Whereas the plasma elimination half-life of ketoprofen and flurbiprofen are similar to that of ibuprofen (1.5-2.5 h and 2.4-4 h, respectively), naproxen is eliminated much more slowly with a half-life of 13-15 h. 

Figure 2.2 Log flux-pH profiles at dosing concentrations (a) ketoprofen (acid, pKa 3.98), dose 75 mg (b) verapamil (base, pKa 9.07), dose 180 mg (c) piroxicam (ampholyte, pKa 5.07, 2.33), dose 20 mg. The permeability and the concentration of the uncharged species are denoted Po and Co, respectively. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

In solutions saturated (i.e., excess solid present) at some pH, the plot of log Co versus pH for an ionizable molecule is extraordinarily simple in form it is a combination of straight segments, joined at points of discontinuity indicating the boundary between the saturated state and the state of complete dissolution. The pH of these junction points is dependent on the dose used in the calculation, and the maximum value of log Co is always equal to log. Sb in a saturated solution. [26] Figure 2.2 illustrates this idea using ketoprofen as an example of an acid, verapamil as a base, and piroxicam as an ampholyte. In the three cases, the assumed concentrations in the calculation were set to the respective doses [26], For an acid, log Co (dashed curve in Fig. 2.2a) is a horizontal line (log Co = log So) in the saturated solution (at low pH), and decreases with a slope of —1 in the pH domain where the solute is dissolved completely. For a base (Fig. 2.2b) the plot of log Co versus pH is also a horizontal line at high pH in a saturated solution and is a line with a slope of +1 for pH values less than the pH of the onset of precipitation. 

GI absorption of many poorly soluble drugs depends on small intestinal transit, as demonstrated for ketoprofen, nifedipine, haloperidol, miconazole, and others. Small intestinal transit rate and transit time become important factors in drug absorption, particularly when the ratio of dose to solubility is high and dissolution rate is very slow or when the drug is... 

Eideriy Age appears to increase the possibility of adverse reactions to NSAIDs. The risk of serious ulcer disease is increased this risk appears to increase with dose. Ketorolac is cleared more slowly by the elderly use caution and reduce dosage. Pregnancy Category B (ketoprofen, naproxen, naproxen sodium, flurbiprofen, diclofenac, fenoprofen, ibuprofen, indomethacin, meclofenamate, sulindac). 

Ketoprofen (2-(3-benzoylphenyl)propionic acid), one of the most active non-steroidal antiinflammatory drugs, is employed in the long-term treatment of rheumatoid arthritis and also as an analgesic in the treatment of pain of varying origins [1]. Clinical use, however, requires a dose schedule of 100-200 mg 3-4 times a day, the duration of action of a single oral dose being only 6-8 h [2]. 

The proper dose of ketoprofen for an optimized zero-order model to obtain the desired drug level pattern to remain in the therapeutic range for 12 h (twice-a-day formulation) was estimated from drug pharmacokinetic parameters [6] by conventional equations [3] on the basis of a one-compartment open model and was found to be 1 lOmg. 

Clinical use Ketoprofen (Hommeril et al., 1994) is a nonsteroidal anti-inflammatory drug used for the treatment of a variety of acute and chronic pain and inflammatory conditions including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, postoperative pain and dysmenorrhoea. It is given by oral, rectal, topical or intramuscular application (100-200 mg/day, maximal dose 300 mg/day) as the sodium or lysine salt. 

The influence of a single dose of omeprazole on the pharmacokinetics of enteric-coated ketoprofen tablets was tested [65], There was no significant difference with or without single-dose omeprazole administration for the systemic bioavailability of the ketoprofen products. A trend in higher plasma concentrations with omeprazole indicates a possibility of drug release from enteric-coated products at potentially elevated stomach pH values. 

Figure 6.13 Fraction of dose absorbed vs. An. The solid line represents results for 24, 500 MCS and the points the experimental data. Key A D-glucose B ketoprofen C naproxen D antipyrine E piroxicam F L-leucine G phenylalanine H beserazide I L-dopa J propranolol K metoprolol L terbutaline M...

Figure 6.17 The classification of 42 drugs in the (solubility-dose ratio, apparent permeability) plane of the QBCS. The intersection of the dashed lines drawn at the cutoff points form the region of the borderline drugs. Key 1 acetyl salicylic acid 2 atenolol 3 caffeine 4 carbamazepine 5 chlorpheniramine 6 chlorothiazide 7 cimetidine 8 clonidine 9 corticosterone 10 desipramine 11 dexamethasone 12 diazepam 13 digoxin 14 diltiazem 15 disopyramide 16 furosemide 17 gancidovir 18 glycine 19 grizeofulvin 20 hydrochlorothiazide 21 hydrocortisone 22 ibuprofen 23 indomethacine 24 ketoprofen 25 mannitol 26 metoprolol 27 naproxen 28 panadiplon 29 phenytoin 30 piroxicam 31 propanolol 32 quinidine 33 ranitidine 34 salicylic acid 35 saquinavir 36 scopolamine 37 sulfasalazine 38 sulpiride 39 testosterone 40 theophylline 41 verapamil HC1 42 zidovudine.

F. Jamali, N. N. Singh, E M. Easutto, R. T. Courts, and A. S. Russell, "Pharmacokinetics of ibuprofen enantiomers in man following oral administration of tablets with different absorption rates," Pharm. Res., 5 40-43 (1988), R. T. Foster, E Jamali, A. S. Russell, and S. R. AlbeUa, "Pharmacokinetics of ketoprofen enantiomers in young and elderly arthritic patients following single and multiple doses," ]. Pharm. ScL, 77 191-195 (1988). 

Foster, R.T. Jamah, F. Russell, A.S. Alballa, S.R. Pharmacokinetics of ketoprofen enantiomers in young and elderly arthritic patients following single and multiple doses. J. Pharm. Sci. 1988, 77 (3), 191-195. 

There are very few data on the gastrointestinal toxicity of over-the-counter doses of ketoprofen. In an endoscopic short-term study in healthy subjects ketoprofen was associated with significant gastrointestinal toxicity (9). Another endoscopic study showed that the i -enantiomer of ketoprofen has less gastrointestinal toxicity than the racemic mixture or the 5-enantiomer while retaining good analgesic activity (SEDA-22,116). 

Lanza FL, Codispoti JR, Nelson EB. An endoscopic comparison of gastroduodenal injury with over-the-counter doses of ketoprofen and acetaminophen. Am J Gastroenterol 1998 93(7) 1051. ... 

The pharmacokinetics of ketoprofen has also been studied in neonatal foals. Neonatal foals clear ketoprofen more slowly and have a larger than adult horses (VVilcke et al 1998). It is important to note that these studies were carried out in healthy normal foals and that pharmacokinetic parameters could be altered in sick or compromised foals. Nevertheless, the results of these studies suggest that the initial dose of ketoprofen may need to be increased in neonatal foals and the subsequent dosing interval increased in order to produce plasma concentrations comparable to adults (Wilcke et al 1998). 

The mechanisms of action of ketoprofen have not been definitively proven in the horse, although ketoprofen has been shown to inhibit COX enzymes. Several studies carried out in horses have shown that ketoprofen, administered at doses that significantly inhibited PG production, had no effect on LT production (Landoni Lees 1995a, Owens et al 1995a) and, therefore, appears not to have any significant effect on lipoxygenase activity. 

Pharmacokinetics of ketoprofen after multiple i.v. doses to mares. Journal of Veterinary Pharmacology and Therapeutics 18 108-116 Schary W L, Lewis R J, Rowland M 1975... 

Ketoprofen. Ketoprofen, 3-bcnzuyl-a mclhylbcnzcne-acetie acid, i -benzoylhydratropic acid (Orudis), is closely related to fenoprofen in structure, properties, and indications. It has a low incidence of. side effects and has heen approved for over-the-counter sale (Orudis KT, Actron). It is available as eapsules and tablets (25 and 50 mg), with a recommended daily dose of 150 to 300 mg divided into three or four doses. It is also available as extended-release capsules (100. 150, and 200 mg). 

Geisslinger, G., Menzel, S., Wissel, K. and Brune, K. (1995) Pharmacokinetics of ketoprofen enantiomers after different doses of the racemate. British Journal of Clinical Pharmacology, 40, 73-75. 

Biomimetic artificiai membranes-factors Effects of pH and co-solvents on the BAMPA were investigated to determine the optimal conditions for the prediction of oral absorption. The permeability (Pam) of 33 structurally diverse drugs to the PC/PE/ PS/PI/CHO/1,7-octadiene membrane system [bio-mimetic lipid (BML) membrane] was measured at pH 5.5,6.5, and 7.4. The pH dependence of Pam was in accordance with the pH partition theory. The better prediction of oral absorption (fraction of a dose absorbed) was shown under the pH 5.5 condition for determining the permeability of poorly soluble compounds were examined. Dimethysulfoxide (DMSO), ethanol (EtOH) and polyoxyethyleneglycol 400 (PEG 400) were added up to 30% to the transport medium as solubilizers. DMSO, EtOH and PEG 400 decreased Pam of hydrocortisone and propranolol. For example, DMSO (30%) decreased Pam of hydrocortisone and propanol by 60 and 70%2, respectively. DMSO and PEG 400 also decreased Pam of ketoprofen. In contrast, EtOH produced an opposite effect on permeability, that is, an increased Pam of ketoprofen. Therefore, the high concentration of these co-solvents could lead to the under- or overestimation of drug permeability. 

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