B. Bannwarth

Diffusion of intramuscular ketoprofen into the cerebrospinal fluid

SummarySerum and cerebrospinal fluid (CSF) concentrations of ketoprofen have been measured in 36 patients hospitalised for sciatica. Diagnostic lumbar puncture was done 15 min to 13 h after a single 100 mg intramuscular dose of ketoprofen. Serum and CSF were sampled at the same time. Free serum concentrations were determined by equilibrium dialysis. Total and free concentrations were assayed by a highly sensitive and specific HPLC method. Ketoprofen rapidly crossed the blood-brain barrier and was detected in CSF 15 min after its administration. The rapid diffusion can be explained by the high lipid solubility of the drug. The CSF level was in equilibrium with the free serum concentration from the second to the 13th hours.

Pharmacological aspects of chiral nonsteroidal anti-inflammatory drugs

Summary— Most NSAIDs are chiral molecules: they exist under 2 configurations of non‐superimposable mirror images which are termed enantiomers or optical isomers or optical antipodes. Direct or indirect (resolution) methods are used to separate this equal mixture of compounds. Some of the enantiomers of the NSAIDs are able to undergo chiral inversion from the inactive R(‐) to the active S(+) form. The pharmacokinetics in terms of absorption, distribution, metabolism, protein binding and elimination may be different for the 2 enantiomers, leading to interindividual variability in clinical response and drug toxicity.

Identification and simultaneous determination of non-steroidal anti-inflammatory drugs using high-performance liquid chromatography

An isocratic high-performance liquid chromatographic procedure is presented for the screening of plasma samples for the presence of sixteen non-steroidal anti-inflammatory drugs. Detection was achieved simultaneously at two wavelengths (254 and 370 nm) and the purity of the eluted peaks was tested using absorbance ratios at the two wavelengths; identification could thus be effective without interferences from substances of other pharmacological classes. The drugs were extracted simultaneously with diethyl ether after acidification and separated from each other on an octadecyl reversed-phase column using only one eluent, acetonitrile-0.3% acetic acid-tetrahydrofuran (36:63.1:0.9, v/v). The recovery, precision and reproducibility of the method were satisfactory as it allowed the determination of the drugs from infra- to supratherapeutic concentrations.

Determination of 2-mercaptopropionylglycine and its metabolite, 2-mercaptopropionic acid, in plasma by ion-pair reversed-phase high-performance liquid chromatography with post-column derivatization

A simple and fast high-performance liquid chromatographic method was developed for the simultaneous measurement of 2-mercaptopropionylglycine (Tiopronine) and its metabolite (2-mercaptopropionic acid) in human plasma after the administration of a pharmaceutical dosage form (Acadione). The sample treatment before high-performance liquid chromatographic analysis consisted of the reduction of the corresponding disulphides by tri-n-butylphosphine and protein precipitation with ethanol. Separation was achieved by ion-pair high-performance liquid chromatography on a reversed-phase column (LiChrospher RP 18e) with cetrimonium bromide as counter ion and detection by fluorimetry after post-column derivatization with a selective thiol reagent, i.e. pyrenemaleimide. The high frequency of the analyzed samples and validation results make the method suitable for pharmacokinetic studies, and this was demonstrated by the first results obtained after the administration of an oral dose of 500 mg of Tiopronine to two healthy subjects.

The effect of food on the systemic availability of ketoprofen

SummaryWe have studied the pharmacokinetics of ketoprofen, a non-steroidal anti-inflammatory drug, in 12 patients after a single 100 mg oral dose both in fasting conditions and with a meal. Food significantly affected the peak plasma concentration of ketoprofen and decreased its absorption rate. However, the extent of absorption of ketoprofen, as reflected by the area under the plasma concentration time curve, appeared to be unchanged in the presence of food.

Tenoxicam concentrations in synovium and joint cartilage in humans

Tenoxicam is an NSAID of the oxicam group. Its distribution in articular tissues was investigated in 12 patients who required total arthroplasty of the hip. They were given tenoxicam 20 mg once daily for 8 to 30 days before surgery. Blood, synovium and cartilage samples were taken concurrently during surgery, about 14 hours after the last tenoxicam dose. The tissues were ground using a freeze grinder. Tenoxicam was assayed by HPLC. Tenoxicam concentrations averaged 6.21±3.81 μg/ml in plasma, 7.56±4.67 μg/g in synovium and 2.05±1.43 μg/g in cartilage. The individual synovium/cartilage ratios ranged from 1.9 to 9.7. Finally tenoxicam exhibited more affinity for its target organ (synovial tissue) than for joint cartilage.

Protein binding of indomethacin in human cerebrospinal fluid.

The binding of the non-steroidal anti-inflammatory drug indomethacin to proteins in human cerebrospinal fluid (CSF), drawn during lumbar puncture from 10 patients affected by lumbosciatica, was measured by equilibrium dialysis and spectrofluorimetry. Similar binding studies on human serum albumin solutions (0.5 and 1 g/L) were performed using the same techniques. The mean binding percentage of indomethacin determined by equilibrium dialysis was 40%. The results obtained by both techniques allowed us to conclude that the binding of indomethacin in CSF was essentially due to albumin.

Stereoselective distribution of tiaprofenic acid in synovium and cartilage in osteoarthritic patients

Objective: In order to document the stereoselective distribution in joints of a chiral nonsteroidal anti-inflammatory drug, the relative affinities of the enantiomers of tiaprofenic acid in synovium and for cartilage were compared.Methods:The distribution of tiaprofenic acid in synovium and in cartilage was studied 25 h after administering the racemic drug for 2 days (600 mg of a sustained-release preparation, once daily), in 12 inpatients with osteoarthritis of the hip requiring arthroplasty. Enantiomers were quantified in plasma and freeze-ground tissues by a chiral HPLC assay.Results:Plasma concentrations of the dextrorotatory (R) enantiomer (0.40 μg/ml) were higher than those of its antipode. The concentration of racemate in synovium (in dried and fresh tissues, 150% and 40%, respectively, of the concentration in plasma) was much higher than that in cartilage (in dried tissues 32% of the plasma concentration). The ratio of the active, dextrorotatory (R) enantiomer to its antipode was higher in synovial tissue than in plasma.Conclusion:Tiaprofenic acid is distributed stereoselectively in plasma and synovium, which contain a higher concentration of the active, dextrorotatory (R) enantiomer. In cartilage, it reaches only a very low concentration.

Effect of age on the disposition of sodium fluoride

SummarySodium fluoride (NaF) is used in the treatment of axial osteoporosis and so is mostly given to old patients. Since its pharmacokinetics has not been studied in the elderly, the pharmacokinetics of an enteric-coated tablet containing 50 mg NaF has been investigated in 15 aged inpatients (aged 65 to 75 y) and 12 young healthy volunteers (aged 21 to 26 y).The serum AUC of fluoride was 1.7-time higher in older than in younger subjects. There was a strong inverse correlation between the AUC and either body surface area (BSA) or glomerular filtration rate (GFR), both of which were very much lower in the elderly.This concluded that if efficacy or safety are related to the bioavailability of fluoride, it maybe valuable to adjust the dosage of fluoride accordingly to the GFR and BSA.

Effect of dimethicone (polysilane gel) on the stereoselective pharmacokinetics of ketoprofen

AbstractObjective: Since dimethicone may be employed to improve gastrointestinal tolerability of non steroidal anti-inflammatory drugs (NSAIDs), we studied its influence on the pharmacokinetics of ketoprofen in subjects receiving a single oral dose of racemic ketoprofen. Patients and methods: In a cross-over experimental design, 12 healthy fasting volunteers were given a single oral dose (100 mg) of racemic ketoprofen, administered with or without dimethicone. The kinetic parameters measured were area under the concentration (AUC), maximum peak plasma concentration (Cmax), time to reach peak concentration (tmax), elimination half-life (t1/2), mean residence time (MRT) and urinary excretion for R and S enantiomers. Results: Dimethicone reduced the peak concentration of both R and S ketoprofen by about 10% (P < 0.05) and also induced a slight but non-significant increase in the mean time to achieve peak concentration. However, this treatment had no significant effect on the bioavailability and the elimination of R and S enantiomers, as shown by AUC, t1/2 and MRT values. The absorption patterns were equivalent for both ketoprofen isomers, since plasma pharmacokinetic parameters were similar. Nevertheless, the urinary recovery was significantly lower for R ketoprofen than for its antipode. The administration of dimethicone did not alter this stereoselectivity. Conclusion: The administration of dimethicone to alleviate the epigastralgic effects related to NSAIDs does not affect the efficacy of the treatment. Dimethicone did not significantly alter the bioavailability of ketoprofen, chosen as an example of an NSAID, especially that of the pharmacologically active S enantiomer.