Propranolol Diclofenac

Among pharmacenticals, EE2 has been the snbject of particular recent attention becanse of its ability to canse endocrine disrnption in fish, as has been described in Chapter 15. Low levels of mixtnres of beta blockers, such as propranolol, metoprol, and nadolol have been detected in snrface waters, and there have been investigations of their possible effects on aqnatic invertebrates (Huggett et al. 2002). Veterinary medicines, too, have come nnder scrntiny for example, the dramatic effects of diclofenac on vnltnres, which will be discnssed shortly. Many questions remain to be answered abont the possible ecological effects of complex mixtures of pharmaceuticals and veterinary medicines. 

Fig. 2.1. Lipophilicity profiles for diclofenac (acid), propranolol (base) and morphine (ampholyte). Dashed lines indicate the pH range where molecule may partition in its ionized form.

Alnouti et al. (2005) used Symbiosis to measure propranolol and diclofenac in rat plasma. Twelve different SPE cartridges were screened. A C18 HD (2 x 10 mm inner diameter, Spark) was chosen because it provided the best recovery and peak shapes. When a Luna C18 (2.1 x 50 mm, 5 /an, Phenomenex) was used, the run time was 4 min it was 2 min when a monolithic Chromolith C18 (50 x 2.1 mm, Merck KgaA) column was used. 

Online IS introduction allows loading of samples in the biological matrix without preparation. ISs were introduced online in the quantitation of propranolol and diclofenac in plasma (Alnouti et al. 2006). Plasma samples were loaded into the autosampler without pretreatment. Both the plasma sample (10 /iL) and IS (5 //I. from an IS microreservoir) were aspirated into an injection needle sequentially and injected into the sample loop. After the switching of an injection valve, the mixed solution in the sample loop was loaded into a cartridge containing washing solution for online SPE. The accuracy and precision of the online IS method were comparable (85 to 119% and 2 to 12%, respectively) to values obtained offline (86 to 106% and 2 to 16%, respectively). 

All chemicals were used as received. PDADMAC and PAMPS were obtained from Aldrich Chemical Co. (Milwaukee, WI). Diclofenac sodium, sodium sulfathiazole, labetalol HCl, propranolol HCl, verapamil HCl, and diltiazem HCl were purchased from Sigma Chemical (St. Louis, MO). Dextrose USP was obtained from Amend Co. (Irvinton, NJ). Water was distilled and deionized using a Nanopure purihcation system (Fischer Scientihc, Fair Lawn, NJ). Simulated intestinal fluid was prepared using a O.OIM phosphate buffer (sodium phosphate monobasic and potassium phosphate dibasic) at pH 7 and 5.5 with different amounts of NaCl to vary the ionic strength. Simulated gastric fluid (pH 1.5) was prepared with concentrated HCl with different amounts of NaCl to vary the ionic strength. 

The release kinetics from the tablets of the drug-polymer complexes were carried out in buffered release media containing 0.01 M phosphate and NaCl ranging from 0.2 M to 0.02 M at 37°C by the USP basket method at 100 rpm. Drug release was monitored on a HP 8452A diode-array spectrophotometer at 250, 306, 306, 270, 278, 278, and 274 nm for sodium diclofenac and sulfathiazole, labetalol HCl, propranolol HCl, verapamil HCl, and diltiazem HCl, respectively. 

For highly potent APIs, profound effects can occur at low ng levels, the adverse effect of ethynylestradiol on fish populations is one example [107]. Another example is the development of resistant bacterial strains induced by the release of antibiotics into the environment [112, 113]. Dome et al. [114] concluded that fluoxetine, ibuprofen, diclofenac, propranolol and metoprolol exhibit relatively high acute toxicity to aquatic species. In addition, due to the inherent properties of these chemicals, pharmacodynamic effects were observed in the heart rate of Daphnia magna for the (3-blockers propranolol and metoprolol. 

Figure 1.30. LC-MS/MS (MRM) chromatograms of (a) propranolol (260—>116)/ketoconazole (531 489) and (b) diclofenac (294, 250)/ibuprofen (205. 161) in rat plasma obtained with online SPE and either a Luna C18 column (left panels) or a Chromolith monolithic column (right panels) combination. (Reprinted with permission from Alnouti et at., 2005.)...

Maitani, Y., A. Coutel-Egros, Y. Obata, and T. Nagai. 1993. Prediction of skin permeabilities of diclofenac and propranolol from theoretical partition coefficients determined from cohesion parameters. ]. Pharm. Sci. 82(4) 416-420. 

Fig. 2.1 Schematic drawing of the so-called piston theory showing the partitioning into DOPC liposomes of (A) propranolol in high-pH medium, (B) diclofenac in low-pH medium, (C) propranolol in low-pH medium, and (D) diclofenac in high-pH medium. (Reprinted from Fig. 3 of ref. 43 with permission from Kluwer Academic/Plenum Publishers.)...

Sotalol, metoprolol, propranolol, carvedilol, nifedipine, captopril, cilazapril, milrinone, ticlopidine, acenocoumarol, furosemide, acetylsalicylic acid, salicylic acid, ibuprofen, naproxen, ketoprofen, diclofenac, paracetamol, dipyrone, mildronate, sildenafil, dexa-methasone, carbamazepine, terbinafine/urine UHPLC MS/MS Column Zorbax Rapid Resolution High Definition SB-C18 (50 x 2.1 mm, 1.8 pm) Mobile phase Solvent A 0.1 % HCOOH in water Solvent B MeOH (gradient elution) Detection MS/MS, ionization ESI Protein precipitation LOQ 0.05-0.60 ng/mL [71]... 

Aliskiren, prasugrel, rivaroxaban, prednisolone, propranolol, ketoprofen, nifedipine, naproxen, terbinafine, ibuprofen, diclofenac, sildenafil, acenocoumarol/urine UHPLC UV Column Poroshell 120EC-Ci8 (100 X 3.0 mm 2.7 pm) Mobile phase Solvent A 0.05 % TFA in water Solvent B ACN (gradient elution) Detection 2 = 221, 228, 230, 240, 250, 275, 280 nm Extraction SPE/column CgHs/elution MeOH LOD 0.003-0.217 pg/mL LOQ 0.01-0.650 pg/mL [75]... 

Figure 17.14 Semi-empirical HOMO orbital calculations on the aromatic substrates, propranolol (left) and diclofenac (right), used to predict the hkely sites of hydroxylation.

DMSO X 5 X Sulfasalazine, furosemide, atenolol, acetaminophen, propranolol, theophylline, diclofenac, metoprolol, antipyrine, naproxen Watanabe etak, 2004... 

Also analyzed acebutolol, acepromazine, acetaminophen, acetazolamide, acetophenazine, albuterol, amitriptyline, amobarbital, amoxapine, antipsrrine, atenolol, atropine, azata-dine, baclofen, benzocaine, bromocriptine, brompheniramine, brotizolam, bupivacaine, buspirone, butabarbital, butalbital, caffeine, carbamazepine, cetirizine, chlorqyclizine, chlordiazepoxide, chlormezanone, chloroquine, chlorpheniramine, chlorpromazine, chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone, cimetidine, cisapride, clomipramine, clonazepam, clonidine, clozapine, cocaine, codeine, colchicine, qyclizine, (yclo-benzaprine, dantrolene, desipramine, diazepam, diclofenac, diflunisal, diltiazem, diphenhydramine, diphenidol, dipheno late, dipyridamole, disopyramide, dobutamine, doxapram, doxepin, droperidol, encainide, ethidium bromide, ethopropazine, fenoprofen, fentanyl, flavoxate, fluoxetine, fluphenazine, flurazepam, flurbiprofen, fluvoxamine, fii-rosemide, glutethimide, glyburide, guaifenesin, haloperidol, homatropine, hydralazine, hydrochlorothiazide, hydrocodone, hydromorphone, hydro g chloroquine, hydroxyzine, ibuprofen, imipramine, indomethacin, ketoconazole, ketoprofen, ketorolac, labetalol, le-vorphanol, lidocaine, loratadine, lorazepam, lovastatin, loxapine, mazindol, mefenamic acid, meperidine, mephenytoin, mepivacaine, mesoridazine, metaproterenol, methadone, methdilazine, methocarbamol, methotrexate, methotrimeprazine, methoxamine, methyl-dopa, methylphenidate, metoclopramide, metolazone, metoprolol, metronidazole, midazolam, moclobemide, morphine, nadolol, nalbuphine, naloxone, naphazoline, naproxen, nifedipine, nizatidine, norepinephrine, nortriptyline, oxazepam, oxycodone, oxymetazo-line, paroxetine, pemoline, pentazocine, pentobarbital, pentoxifylline, perphenazine, pheniramine, phenobarbital, phenol, phenolphthalein, phentolamine, phenylbutazone, phenyltoloxamine, phenytoin, pimozide, pindolol, piroxicam, pramoxine, prazepam, prazosin, probenecid, procainamide, procaine, prochlorperazine, procyclidine, promazine, promethazine, propafenone, propantheline, propiomazine, propofol, propranolol, protriptyline, quazepam, quinidine, quinine, racemethorphan, ranitidine, remoxipride, risperidone, salicylic acid, scopolamine, secobarbital, sertraline, sotalol, spironolactone, sulfinpyrazone, sulindac, temazepam, terbutaline, terfenadine, tetracaine, theophylline, thiethyl-perazine, thiopental, thioridazine, thiothixene, timolol, tocainide, tolbutamide, tolmetin, trazodone, triamterene, triazolam, trifluoperazine, triflupromazine, trimeprazine, trimethoprim, trimipramine, verapamil, warfarin, xylometazoline, yohimbine, zopiclone... 

Also analyzed acebutolol, acetaminophen, alprazolam, amphetamine, atenolol, betaxolol, brotizolam, caffeine, camazepam, captopril, chloroquine, clobazam, clomipramine, cloth-iapine, clotiazepam, cloxazolam, cocaine, codeine, diclofenac, dihydralazine, dihydrocodeine, dihydroergotamine, diphenhydramine, domperidone, doxepin, droperidol, ergota-mine, ethyl loflazepate, fenethylline, fluoxetine, flupentixol, flurazepam, furosemide, gliclazide, hydrochlorothiazide, hydroxyzine, ibuprofen, imipramine, ketazolam, loprazo-1am, lorazepam, lormetazepam, maprotUine, medazepam, mepyramine, methadone, methaqualone, methyldopa, methylphenidate, metoclopramide, metoprolol, mexiletine, mianserin, midazolam, minoxidil, morphine, nadolol, nitrazepam, oxprenolol, papaverine, pentazocine, phenprocoumon, phenylbutazone, pipamperone, piritramide, practolol, pra-zepam, prazosin, promazine, promethazine, propoxyphene, propranolol, prothipendyl, quinine, sotalol, sulpride, thioridazine, trazodone, triazolam, trimipramine, tripelennamine, lyramine, verapeunil, yohimbine... 

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