Disposition of suprofen enantiomers in the cat.

Suprofen (SPF) is a non-steroidal anti-inflammatory drug (NSAID), which belongs to the 2-arylpropionic acids subclass. As a result of their chiral characteristics, these compounds have shown a marked enantioselective behaviour with a high degree of interspecies variation. They are mainly eliminated by glucuronidation. Plasma, biliary and urine disposition of SPF was investigated in the cat after intravenous administration of the racemate (dose 2 mg/kg). Both enantiomers exhibited similar disposition profiles in plasma with no evidence of chiral inversion. During bile sampling time, recovered acylglucuronides of R (-) and S (+) SPF were less than 1% of the total dose administered. Only free SPF was recovered in the urine, representing 0.12% of the administered racemic SPF dose. The results indicate that neither chiral inversion nor glucuronidation predominate in SPF disposition in cats.

Determination of the enantiomers of suprofen and [2H3]suprofen in plasma by capillary gas chromatography-mass spectrometry.

A method for the stereoselective assay of the (+)- and (-)-enantiomers of suprofen and [2H3]suprofen in human plasma was developed using gas chromatography-mass spectrometry-selected-ion monitoring. (+/-)-[2H7]Suprofen was used as an internal standard. The method involved diethyl ether extraction and chiral derivatization with S-(-)-1-(naphthyl)ethylamine to form diastereomeric amide. The diastereoisomers were separated on a capillary gas chromatograph-mass spectrometer. Quantitation was achieved by selected-ion monitoring of the quasi-molecular ions of the diastereoisomers. The sensitivity, specificity, accuracy and reproducibility of the method were demonstrated to be satisfactory for application to pharmacokinetic studies of suprofen enantiomers.

Immune hemolytic anemia associated with tolmetin and suprofen.

This article reports the first case of immune hemolytic anemia possibly associated with the ingestion of suprofen. The patient suffered from massive hemoglobinuria and acute renal failure. Serologic studies of the patient's serum revealed suprofen-dependent red cell antibodies. However, tolmetin-dependent antibodies were also found in the serum, showing the same properties as the suprofen antibodies and an even higher titer. The patient not only had drug-dependent antibodies in the serum, but also had developed autoantibodies, a phenomenon that has been described for several other drugs. The working mechanism by which suprofen and tolmetin caused immune hemolysis had properties of both the immune complex model and the induction of autoimmunity. Although it was unclear whether the immune hemolytic anemia was the result of suprofen, tolmetin, or cross-reacting antibodies, we feel that suprofen should be added to the list of nonsteroidal anti-inflammatory drugs associated with a positive direct antiglobulin test.

In vitro-in vivo correlation exemplified by sustained release formulations of suprofen.

To evaluate some prototype oral sustained release formulations of the analgesic drug suprofen (alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid, Suprol) in vitro-in vivo correlations were performed. Numerical deconvolution led to hypothetical in vivo absorption curves which were in close agreement with the in vitro dissolution profiles. Furthermore, a linear correlation was obtained between the in vivo and in vitro mean residence times calculated from the blood level data.

Species differences in the metabolism of suprofen in laboratory animals and man.

The metabolism of the oral anti-inflammatory agent suprofen (S), 2-4-(2-thienylcarbonyl)phenyl)propionic acid, has been studied in mice, rats, guinea pigs, dogs, monkeys, and human volunteers. The major metabolites of S in the serum, urine, and feces of these species were determined by GC/MS and HPLC techniques. The metabolic pathways of S in these species involved reduction of the ketone group to an alcohol (S-OH), hydroxylation of the thiophene ring (T-OH), elimination of the thiophene ring to a dicarboxylic acid (S-COOH), and conjugation with glucuronic acid or taurine. In 72-hr urine and feces of these species after po dosing of 1.6 to 2 mg/kg of S, S and these metabolites accounted for 46 to 92% of the dose and were mainly excreted in the urine. S was present as a major product (excreted mainly in conjugated form) in all species. S-OH was a major component in guinea pig and dog but a minor one in other species. T-OH was identified as a major metabolite in monkey, rat, mouse, and man, but a minor one in guinea pig, and it was absent in the dog. S-COOH was present as the minor metabolite in mouse and rat, and present at trace levels in dog, monkey, and man. Conjugation of the propionic acid functionality with taurine was observed only in the dog; in the other species, conjugation with glucuronic acid was extensive. Absorption parameters of S in the rat and monkey were similar to those in man; however, other species were very different from man.

Pharmacokinetics and tolerability of suprofen. Experience with intramuscular application in healthy volunteers.

In the present randomized single-blind study local and systemic tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) 200 mg/ml i.m. were compared with those of diclofenac 25 mg/ml and placebo. The three treatment groups consisted of 15 patients each and were homogeneous with respect to demographic parameters. The volunteers were assigned to these groups in random fashion and underwent treatment with 3 injections/day of either suprofen or diclofenac or placebo for 7 days. Mild local pain or systemic intolerance signs were equally rare in all three groups. The laboratory tests with the three preparations studied failed to indicate any negative influence on the hematopoietic organs or the adrenal activity. Abnormal changes in the ECG and the cardiovascular parameters during the treatment were not observed. Moderately or slightly elevated SGOT and SGPT values were seen during treatment with suprofen; however, these values returned to normal after the treatment. As compared with these elevations the values for subjects on diclofenac were higher and did not return to normal within 5 days following withdrawal of the drug. Moreover, the creatine phosphokinase activity, observed in both the suprofen and the diclofenac group, was so extremely high in subjects on diclofenac that this drug had to extremely high in subjects on diclofenac that this drug had to be withdrawn on day 4 of the study. On the basis of these results it can be stated that intramuscular injections of suprofen 200 mg/ml are locally and systemically well tolerated even on administration t.i.d. Measurement of the steady-state plasma level was not indicative of altered kinetic behaviour of suprofen. The plasma levels remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Local and systemic tolerability of suprofen. Experience with intravenous administration and infusion in healthy volunteers (2nd comm.).

12 healthy male volunteers who had given consent to the study each received in a randomized cross-over design 13 applications of 2-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) injection solution 200 mg/ml at 8 a.m. and at 2 p.m. as i.v. bolus injections or as infusions. It could be demonstrated, that suprofen given as multiple dose i.v. bolus injections or as multiple infusion doses was well tolerated. The peak plasma concentrations after i.v. bolus injections were in the range of 16.3 to 42.3 micrograms/ml (mean 26.5) and after 2 h between 1.3 and 9.8 micrograms/ml (mean 3.2). 1.5 h after the start of infusion (end of the infusion) the plasma concentrations were in the range of 4.0 and 11.2 micrograms/ml (mean 7.2) with a infusion rate of 4.6 mg/min for the first 30 min and then of 1.1 mg/min for about 57 additional min. At 2.5 h after the infusion applications the mean plasma level was 2.0 micrograms/ml. There was no indication of accumulation nor accelerated elimination during the 7-day period. There was no statistically significant difference between the plasma elimination after the last injection of the 7-day period and the plasma elimination after i.v. single injection as well as from the elimination after the last infusion of the 7-day period.

Absorption and excretion of suprofen in both sexes of rats, guinea pigs, and rabbits.

DL-2-(4-2-Thienylcarbonyl)phenyl)propionic acid (suprofen) was rapidly absorbed in both sexes of rats, guinea pigs, and rabbits after oral administration. Blood levels after a single dose of 2 mg/kg 3H-suprofen in all the animals reached maxima within 15 min, and elimination of the 3H from blood was rapid; the radioactivity was mostly excreted in the urine and feces within 24 h after dosing.

Suprofen concentrations in human breast milk.

Six healthy females who had been nursing their infants for 6 to 11 months received a single, 200-mg oral dose of suprofen, an analgesic which has been evaluated clinically. Blood and milk samples were collected at discrete times over an 8-hour period and suprofen concentrations in milk and plasma were determined by HPLC. The binding of suprofen to milk and plasma proteins was determined by equilibrium dialysis. The maximum concentrations of suprofen in the milk ranged from 0.118 to 0.232 microgram/ml and occurred from 1 to 2 hours after dose administration. The maximum plasma suprofen concentrations ranged from 13.8 to 28.3 micrograms/ml and occurred from 0.5 to 2 hours after dosing. Within any subject, the peak suprofen concentration in milk was 0.5 to 0.9 per cent of the peak concentration in plasma. Suprofen was extensively bound to plasma proteins (99.4 per cent) and minimally bound to milk proteins (10 per cent). The average milk/plasma ratio based on area-under-the-curve measurements was approximately 0.014, or 1.4 per cent. This ratio agrees well with an estimated value of 1.2 per cent for the pH-dependent, passive diffusion of suprofen from plasma into milk. From these data, it appears that there would be minimal suprofen exposure to a nursing infant after administration of recommended doses to the nursing mother.

Quantitative determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography.

A sensitive, specific and rapid determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography is described. Plasma or urine samples are directly injected into the liquid chromatograph, which consists of commonly available modules. Manual sample cleanup procedures as well as the addition of an internal standard are not needed. Using 20 microliter-aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 1.0 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 99.2% for plasma and 99.7% for urine samples.

High-performance liquid chromatographic assay for suprofen, a potent new analgesic, in plasma.

A simple, rapid, high-performance liquid chromatographic (HPLC) determination of therapeutic levels of suprofen, a potent new analgesic, in human plasma is described. After a simple extraction, the compound is analyzed by HPLC using a reversed-phase column and a UV detector. Quantitation is accomplished using an external standard; peak areas are determined by computer. An average recovery of 80.0 +/- 8.5% SD of the drug was obtained over the 0.2-20.0-microgram/ml range. Maximum sensitivity is approximately 0.1 microgram/ml. No interference is encountered from any known metabolite of suprofen.