Permeability ketoprofen

Class I compounds have both good solubility and permeability and generally offer no problems with regard to having a good absorption profile (e.g., acetaminophen, disopyramide, ketoprofen, metoprolol, nonsteroidal anti-inflammatory agents, valproic acid, verapamil). In general, one would not expect the presence of food to influence the absorption of this class... 

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.]...

The two-component lipid models were also characterized in the absence of sink conditions (Table 7.8). Comparisons between models 7.0 (Table 7.7) and 1.0 (Table 7.5) suggest that negative charge in the absence of sink causes the permeabilities of many of the bases to decrease. Exceptions are quinine, prazosin, primaquine, ranitidine, and especially metoprolol. The inclusion of 0.6% PA causes Pe of metoprolol to increase nearly 10-fold, to a value twice that of propranolol, a more lipophilic molecule than metoprolol (based on the octanol-water scale). Naproxen and ketoprofen become notably more permeable in the two-component system. Surprisingly, the neutral progesterone becomes significantly less permeable in this system. 

The permeabilities of the acid examples rise with increasing phospholipid content, up to 20% lipid, with rank ordering preserved. Naproxen and ketoprofen... 

The above iso-pH measurements are based on the 2% DOPC/dodecane system (model 1.0 over pH 3-10 range). Another membrane model was also explored by us. Table 7.16 lists iso-pH effective permeability measurements using the soy lecithin (20% wt/vol in dodecane) membrane PAMPA (models 17.1, 24.1, and 25.1) The negative membrane charge, the multicomponent phospholipid mixture, and the acceptor sink condition (Table 7.1) result in different intrinsic permeabilities for the probe molecules. Figure 7.40 shows the relationship between the 2% DOPC and the 20% soy iso-pH PAMPA systems for ketoprofen. Since the intrinsic permeability of ketoprofen in the soy lecithin membrane is about 20 times greater than in DOPC membrane, the flat diffusion-limited transport region of the log Pe... 

Figure 7.40 Permeability-pH profiles for ketoprofen under iso-pH conditions for two different PAMPA models unfilled circles = 2% DOPC/dodecane, filled circles = 20% soy lecithin/dodecane. [Reprinted from Avdeef, A., in van de Waterbeemd, H. Lennemas, H. Artursson, P. (Eds.). Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley-VCH Weinheim, 2003 (in press), with permission from Wiley-VCH Verlag GmbH.]...

The strategy for the development of the oral absorption model at pION is illustrated in Fig. 7.58. The human jejunal permeabilities reported by Winiwarter et al. [56] were selected as the in vivo target to simulate by the in vitro model. In particular, three acids, three bases and two nonionized molecules studied by the University of Uppsala group were selected as probes, as shown in Fig. 7.58. They are listed in the descending order of permeabilities in Fig. 7.58. Most peculiar in the ordering is that naproxen, ketoprofen, and piroxicam are at the top of the list, yet these three acids are ionized under in vivo pH conditions and have lipophilicity (log Kj) values near or below zero. The most lipophilic molecules tested, verapamil and carbamazepine... 

Figure 7.59 shows a plot of logP JP (human jejunal permeabilities) vs. log pCaco-2 takgjj from the literature, based on the work of more than 11 laboratories. The r2 for the correlation is 0.62. It is clear from the plot that some laboratories better predicted the HJP than other laboratories. Figure 7.60 shows the plot of the results published by Artursson s group [506,512,603], where r2 was calculated as 0.95, the most impressive value of all the comparisons. It is noteworthy that naproxen, ketoprofen, and piroxicam were not available for the comparison in the Fig. 7.60 plot. 

Table 7.23 shows the results for 47 specific PAMPA models tested at pION, according the the scheme in Fig. 7.58. The two columns on the right are the r2 values in the comparisons. The neutral-lipid models (1.0, 1A.0, 2.0, 3.0, and 4.0) at pH 7.4 do not explain the permeability trend indicated in the human jejunal permeabilities [56]. Octanol was least effective, with r2 0.01. This should not be too surprising, since we did note that the appearance of naproxen, ketoprofen, and piroxicam at the top of the HJP ordering was unexpected. Our expectations were based on the octanol-water lipophilicity scale, which clearly does not correlate with the HJP trend. Adding a sink condition to the 2% DOPC model (model 1.1) improves correlation (r1 increases from 0.33 to 0.53). The addition of cholesterol to the 2% DOPC/dodecane system made the model unstable to the surfactant-created sink condition. 

The permeabilities of the acid examples rise with increasing phospholipid content, up to 20% lipid, with rank ordering preserved (data not shown). Naproxen and ketoprofen show the most dramatic increases in going from 2% to 10% lipid membranes - somewhat higher in soy than in egg. Piroxicam shows less... 

Fig. 3.6. Log permeability-pH profiles of ketoprofen in 2% wt/vol DOPC in dodecane (open circles) and 20% wt/vol soy lecithin in dodecane (filled circles). The weak acid is about 17 times more permeable in soy than in DOPC, as indicated by the calculated intrinsic...

Figure 3.6 compares iso-pH permeabilities of ketoprofen at various pH values in a 2% DOPC-dodecane model (open circles) and the 20% soy lecithin with SLS in the acceptor compartment (filled circles, data in Table 3.5). In the presence of the latter negatively charged lipids (with the make-up similar to that of BBM in Table 3.1), ketoprofen is intrinsically more permeable, by a factor of 17. The UWL limit, indicated by the solid curves in low-pH solutions, and consistent with the permeability Pu 19.8 x 10-6 cm s 1 (log Pu —4.7), masks the true intrinsic permeability of the membranes, P0. However, it is possible to deduce the membrane permeability if the pKa is known. In Fig. 3.6, the bending in the dashed (calculated) curves at pH 4 corresponds to the pKa of the molecule. Due to the UWL, the point of bending is shifted to higher pH values in the solid (measured) curves. The difference between the apparent pKa (pK 5.3 for DOPC and 6.3 for soy) and the true pKa (4.12) is the same as the difference between log P0 and log Pu [23],... 

Internal standards Used to demonstrate method reproducibility. Reference materials, such as the low permeability markers mannitol and atenolol and the high permeability markers metoprolol and ketoprofen, may be used to compare values between laboratories [3, 50]... 

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.

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. 

PAMPA-pKa fiux optimized design (pOD)-permeabiiity Iso-pH mapping unstirred PAMPA was used to measure the effective permeability, Pe, as a function of pH from 3 to 10, of five weak monoprotic acids (ibuprofen, naproxen, ketoprofen, salicylic acid, benzoic acid), an ampholyte (piroxicam), five monoprotic weak bases (imipramine, verapamil, propranolol, phenazopyridine, metoprolol), and a diprotic weak base (quinine). The intrinsic permeability, Po, the UWL permeability, Pu, and the apparent pKa (pKa.fiux) were determined from the pH dependence of log Pg. The underlying permeability-pH equations were derived for multiprotic weak acids, weak bases, and ampholytes. The average thickness of the UWL on each side of the membrane was estimated to be nearly 2000 p, somewhat larger than that found in Caco-2 permeability assays (unstirred). As the UWL thickness in the human intestine is believed to be about forty times smaller, it is critical to correct the in vitro permeability data for the effect of the UWL. Without such correction, the in vitro permeability coefficient of lipophilic molecules would be indicative only of the property of water. In single-pH PAMPA (e.g., pH 7.4), the uncertainty of the UWL contribution can be minimized if a specially selected pH (possibly different from 7.4) were used in the assay. From the analysis of the shapes of the log Pe-pH plots, a method to improve the selection of the assay pH, called pOD-PAMPA, was described and tested. From an optimally selected assay pH, it is possible to estimate Pg, as well as the entire membrane permeability-pH profile. 

Permeabihty coefficients for black rat snake were taken directly from Table II for ibuprofen, naproxen, ketoprofen, deoxycorticosterone, 1 la-hydroxyprogesterone, corticosterone, and hydrocortisone. Permeabihty coefficients for indomethacin and progesterone were not inclnded because they were not measured from aqueous solurion. Permeability coefficients for the parabens were not included because they are idenrical to those reported by Itoh, Xia, et al. (1990). 

Kommuru, T.R. Khan, M.A. Reddy, I.K. Racemate and enantiomers of ketoprofen phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers. J. Pharm. Sci. 1998, 87, 833-840. 

An aqueous extract of rosemary enhanced the permeability of Caco-2 cells to furosemide but not verapamil, meto-prolol, ketoprofen, or paracetamol (Laitinen et al. 2004). 

Rhee GJ, Woo JS, Flwang S-J, Lee YW, Lee CH. Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability. Drug Development and Industrial Pharmacy. 1999 25(6) 717-726. 

Figure 15.6. (A) Correlation between human GIT and Caco-2 permeabihty. GIT permeability values are from Refs. [61-63]. Compounds included in the study are amUoride, antipyrine, amoxicMn, atenolol, carbamazepine, cimetidine, desipramine, furosemide, hydrochlorothiazide, ketoprofen, metoprolol, naproxen, piroxicam, propranolol, and ranitidine. (B) Correlation between human GI permeabihty and artificial membrane permeabihty (hexadecane artificial membrane). Paracehular transported compounds are given in bold.

Figure 15.8. Correlation between apparent membrane permeability (logP., P. in cm/s) and octanol/water logP. This calibration curve has been obtained using V = Vj = 0.3mL, a membrane volume of 3 pL, and an incubation time of 4 hours. Compounds included are benzoic acid, furosemide, ketoprofen, propranolol, warfarin, valsartan, nortryptiline, diclofenac, chlor-...

Although the catalytic activity of T. brassicae CGMCC0574 whole cells in the enantioselective hydrolysis of ketoprofen ester was initially moderate, it was significantly promoted after the cells were pretreated for a few hours in a buffer containing an alcohol as the modulator. This suggested a possible permeability barrier from the cell membrane against the mass transfer of substrates and/or products. Therefore, the permeabilization of the yeast cells was considered to be favorable for the enzymatic resolution of ketoprofen. 

Class 1 (High Permeability, High Solubihty) Albuterol, Allopurinol, Amlodipine (Amlo), AmoxicilUn, Antipyiine, Dexamethasone, Diltiazem, Zidovudine, Isosoibide mononitrate, Ketoprofen, Lamivudine, Levonoigestiel, Levofloxa-cin. Metronidazole, Midazolam, Minocycline, Morphine, Nifedipine, Ofloxacin, Prednisolone, Propylthiouracil, Stavudine, Phenobaibital, Fluconazole, Chiiiin, Enalapril, Acetaminophen, Diazepam, Lsoniazid, Levodopa, Metoprolol, Paracetamol, Pyrazinamide, Salicylic add, Ethirtylestradiol. ... 

There is only a single reference on the effects of rapeseed/canola phenolics on cell permeability. Satu et al. (2005) indicated that the crude rapeseed oil phenolic extract had no significant effect on the permeability of the model drugs. However, rapeseed meal phenolics enhanced the permeability of verapamil and ketoprofen indicating that they may have an impact on drugs and other components being actively transported across the cell membrane. 

---