Pharmacokinetics of flurbiprofen.

Both radiolabeled and nonlabeled drug have been used to study the pharmacokinetics of flurbiprofen (Ansaid, Upjohn). Drug absorption is rapid, drug disappearance half-life is independent of oral dose, and the area under the plasma drug concentration versus time curve increases with increasing oral dose. Elimination of intact drug from the peripheral circulation is biphasic and rapid. Following a single oral dose of 100 mg of flurbiprofen, drug bioavailability is equivalent using regimens of four 25-mg tablets, two 50-mg tablets, or one 100-mg tablet once daily. Long-term administration of flurbiprofen appears neither to inhibit nor induce the drug's metabolism.

Radioimmunoassay for medroxyprogesterone acetate (Provera) using the 11alpha-hydroxy succinyl conjugate.

PIP: The development of a radioimmunoassay for medroxyprogesterone acetate (MPA) employing rabbit antibodies made against a bovine serum albumin (BSA) conjugate of the hemisuccinate ester of 11alpha-hydroxy MPA are described. The 11alpa-hydroxyl group was introduced into MPA by a series of chemical and microbiological transformations. The acid succinate MPA was coupled to BSA by reacting it with N,N'-carbonyldiimidazole. Cross-reactivities of several MPA analogs were compared suing rabbit antisera developed against the C-11 conjugate of MPA and goat antiserum developed against a C-3 conjugate of MPA. Antibodies formed against the C-11 conjugate showed increased specificity to steroid analogs which changes in the C-21 side chain. The profiles of serum MPA levels vs time, measured with both the C-3 and C-11 antisera, after oral drug administration to the monkey were similar. After intramuscular drug administration to dogs, serum MPA levels measured with the C-3 antisera were consistently greater as compared with those with C-11 antisera. Factors affecting precipitation of the antibody-antigen complex, assay precision, and assay sensitivity were evaluated.^ieng

Electron-capture GLC determination of ibuprofen in serum.

To evaluate drug-protein binding, a sensitive method for the determination of ibuprofen in submilliliter amounts of serum was required. A specific and highly sensitive procedure, based on benzene extraction of the acidified specimen. TLC of the benzene extract residue, fomation of the pentafluorobenzyl esters of the materials eluted from the thin-layer chromatogram, and quantification of the pentafluorobenzyl esters by GLC, was developed. Utilizing electron-capture detection, the method is sensitive to 0.1 microgram of ibuprofen/0.1 ml of serum. Statistical analyses indicated an average recovery of 97.7% with a standard deviation of +/- 7.3%. Mass spectrometric analysis, in conjunction with GLC, confirmed the specificity of the method for the intact drug. The procedure was applied successfully to drug absorption and drug-protein binding studies in humans.

GLC determination of ibuprofen [dl-2-(p-isobutylphenyl) propionic acid] enantiomers in biological specimens.

To study the behavior of the d- and l-isomers of ibuprofen in humans, a method for the determination of the individual enantiomers in plasma and urine was required. A specific procedure was developed based on (a) benzene extraction of the acidified specimens, (b) TLC of the benzene extract residue, (c) formation of the l-alpha-methylbenzylamides of the materials eluted from the chromatograms, and (d) quantification of the resulting diastereoisomeric amides by GLC in conjunction with flame-ionization detection. When using a 1-ml aliquot of the specimen, the method is sensitive to 1 mug of each enantiomer/ml of plasma or urine. As compared to simple aqueous solutions, the average recoveries of the enantiomers from plasma and urine ranged from 94 to96%. Mass spectrometric analyses, in conjunction with GLC, confirmed the specificity of the method for the intact enantiomers. The procedure was applied successfully to drug absorption studies in humans. After oral administration of the racemic mixture, the predominant enantiomer in peripheral circulation and excreted in urine was of the d-configuration.

Fluorometric determination of 2,3-bis(p-methoxphenyl)imidazo(1,2-a)pyrimidine in biological materials.

Interest in 2,3-bis(p-methoxyphenyl)imidazo[1,2-a]-pyrimidine as a potent, orally active, anti-inflammatory agent required a method for its determination in serum, urine, and feces to permit studies of its absorption, metabolism, and excretion. A simple, rapid, sensitive, and specific procedure was developed based on an ethyl acetate extraction of alkaline specimens and subsequent fluorometric analysis of ethanolic solutions of the extract residues. The method is sensitive to 0.2 mug/ml, 0.3 mug/ml, and 1.2 mug/100 mg of drug in serum, urine, and feces, respectively. The overall mean recovery and the standard deviation from biological samples are 99.8 +/- 5.1%. The procedure has been successfully applied to absorption studies in the dog.

Fluorometric determination of trifluoromethyl-substituted 2,3-bis(4-methoxyphenyl)indoles in biological materials.

Interest in the 5-, 6-, and 7-trifluoromethyl-substituted 2,3-bis(4-methoxyphenyl)indoles as potent, orally active anti-inflammatory agents required a method for their determination in serum, urine, and feces to permit studies of their absorption, metabolism, and excretion. A simple, rapid, sensitive, and specific procedure was developed based on an ethyl acetate extraction of alkaline specimens and subsequent fluorometric analysis of ethanolic solutions of the extract residues. The method is sensitive to 0.1 microgram/ml, 0.5 microgram/ml, and 0.7 microgram/100 mg of these compounds in serum, urine, and feces, respectively. Overall mean recoveries and standard deviations of the 5-, 6-, and 7-trifluoromethyl-substituted compounds from biological samples were 102.2 +/- 3.0, 102.2 +/- 5.4, and 100.5 +/- 5.7%, respectively. The procedure was applied successfully to absorption studies with 2,3-bis(4-methoxyphenyl)-7-(trifluoromethyl)indole in the dog.

Generic propoxyphene: need for clinical bioavailability evaluation.

Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.

Isomeric inversion of ibuprofen (R)-enantiomer in humans.

Enantiomeric compositions of the major urinary metabolites of ibuprofen [(RS)-2-(4-isobutylphenyl)propionic acid]were characterized after oral administration of the racemic mixture and oral administration of the individual enantiomers to normal human volunteers. Resolution of the diastereomeric amides, formed by reaction of the urinary metabolites with (S)-(-)-alpha-methylbenzylamine, was achieved by GLC. Only the (R)-(-)-enantiomer of the intact drug was inverted to its optical antipode, (S)-(+), in humans. However, both (S)-(+)- and (R)-(-)-enantiomers of the intact drug were transformed independently in vivo to the major metabolites, i.e., 2,4'-(2-hydroxy-2-methylpropyl)phenylpropionic acid and 2,4'-(2-carboxypropyl)phenylpropionic acid. In vivo metabolism of ibuprofen to its carboxy metabolite was not stereoselective.

Endogenous serum testosterone in males after different doses and routes of administration of medroxyprogesterone acetate.

The effects of different doses and routes of administration (oral and IM) of medroxyprogesterone acetate on endogenous testosterone secretion were studied in healthy male volunteers. There were three treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during and after different doses of medroxyprogesterone acetate, were significantly lowered (p < 0.05) in these subjects. A tendency to return toward pretreatment values was noted within three to six weeks after the last dose of medroxyprogesterone acetate. The IM route of administration suppressed the testosterone levels for the longest period of time. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following the course of therapy. No serious or untoward side effects were encountered.

PIP: The effects of different doses and routes of administration (both oral and intramuscular) of medroxyprogesterone acetate on endogenous testosterone secretions were studied in healthy male volunteers. There were 3 treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during, and after different doses of medroxyprogesterone acetate, were significantly lowered (P0.05) in these subjects. A tendency to return toward pretreatment values was noted within 3-6 weeks after the last dose of medroxyprogesterone acetate. Testosterone levels were suppressed for the longest period of time through intramuscular administration. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following therapy. No serious or untoward side effects were encountered.

0-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride as a sensitive derivatizing agent for the electron capture gas liquid chromatographic analysis of keto steroids.

0-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride was used to prepare oximes of steroids with keto groups in selected positions; 3,17 and 20-monoketo; 3,17 and 3,20-diketo. Some of the 3-keto steroids had hindered 17-hydroxyl groups which were not readily amenable to esterification with perfluoroanhydrides, the most commonly used derivatizing agents for electron capture gas chromatographic analysis of hydroxy steroids. The oximes were readily prepared from 5 ng of each of the compounds tested, and with testosterone it was demonstrated that the derivative could be prepared from as little as 0.1 ng. The derivatives were stable to gas chromatography and extremely sensitive to electron capture detection. The sensitivity ranged from 1.5 X 10(4) coulombs per mole of progesterone. Because of the ease of preparation of the derivatives, their stability in common solvents and analytical manipulative techniques, the reagent would be suitable for the micro analysis of biologically significant keto steroids by electron capture gas chromatography.