Chiral Nonsteroidal Anti-inflammatory Drug Research Articles

Stereoselective pharmacokinetics and metabolism of flobufen in guinea pigs.

Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4-(2', 4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac-flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac-flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high-performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R- and S-flobufen. The plasma concentrations of the S- and R-enantiomers differed significantly during the experimental period. The S/R-enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R-flobufen was five times higher than S-flobufen. The other pharmacokinetic parameters (K(e), T(1/2), V(SS)/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4-(2,4-difluorophenyl)-phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long-lasting antiphlogistic and immunomodulatory effects.

Bioavailability of racemic ketoprofen in healthy horses following rectal administration

Ketoprofen (KTP) is a chiral non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, approved by the FDA for the allevation of pain associated with musculoskeletal disorders in horses. The present study was designed to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to healthy horses. One gram of racemic ketoprofen was injected intravenously and administered rectally as a fat based suppository in a cross-over design study (n = 4). Blood samples were analysed for KTP enantiomers using HPLC. AfterIV administration, the S(+) enantiomer concentrations in plasma were higher than the R(–) enantiomer concentrations and the AUC0–12 hfor the S(+) enantiomer was significantly higher than for the R(–) enantiomer. Following rectal administration Cmaxand AUC0–12 hwere significantly higher for the S(+) than for the R(–) enantiomer. Bioavailability after rectal administration was low. Since there was no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(–) to S(+) occurred after rectal administration of racemic KTP to horses.

Effects of R- and S-enantiomers of chiral non-steroidal anti-inflammatory drugs in experimental colitis.

Prostaglandins appear to play an important role in down-regulating intestinal inflammation and promoting repair of injury. In experimental colitis, inhibition of prostaglandin synthesis with nonsteroidal anti-inflammatory drugs (NSAID) leads to marked exacerbation of tissue injury. It has been suggested that the ability of chiral NSAID to inhibit prostaglandin synthesis is completely attributable to the s-enantiomer, while the r-enantiomer is a much weaker inhibitor. Thus, it is possible that r-enantiomers of chiral NSAID will have reduced intestinal toxicity and reduced ability to exacerbate colitis. In the present study, we compared r- and s-enantiomers of two chiral NSAID (flurbiprofen and etodolac) in terms of their ability to exacerbate colitis in the rat. We found that r-flurbiprofen and r-etodolac did not exacerbate colitis, in contrast to the s-enantiomers or racemates. The r-enantiomers also had significantly less inhibitory activity on prostaglandin synthase. Reduced biliary excretion of r-etodolac may have also contributed to the lack of detrimental effects in this model. The results support the hypothesis that prostaglandins play an essential role in down-regulating colonic inflammation and promoting repair.

Effects of R‐ and S‐enantiomers of chiral non‐steroidal anti‐inflammatory drugs in experimental colitis

Prostaglandins appear to play an important role in down‐regulating intestinal inflammation and promoting repair of injury. In experimental colitis, inhibition of prostaglandin synthesis with non‐steroidal anti‐inflammatory drugs (NSAID) leads to marked exacerbation of tissue injury. It has been suggested that the ability of chiral NSAID to inhibit prostaglandin synthesis is completely attributable to the S‐enantiomer, while the R‐enantiomer is a much weaker inhibitor. Thus, it is possible that R‐enantiomers of chiral NSAID will have reduced intestinal toxicity and reduced ability to exacerbate colitis. In the present study, we compared R‐ and S‐enantiomers of two chiral NSAID (flurbiprofen and etodolac) in terms of their ability to exacerbate colitis in the rat. We found that R‐flurbiprofen and R‐etodolac did not exacerbate colitis, in contrast to the S‐enantiomers or racemates. The R‐enantiomers also had significantly less inhibitory activity on prostaglandin synthase. Reduced biliary excretion of R‐etodolac may have also contributed to the lack of detrimental effects in this model. The results support the hypothesis that prostaglandins play an essential role in down‐regulating colonic inflammation and promoting repair.

Passage of S-(+)- and R-(-)-ketoprofen across the human isolated perfused placenta.

Ketoprofen is a chiral non-steroidal anti-inflammatory drug (NSAID) available as a racemic (rac) mixture of S-(+)- and R-(-)-isomers. Its inhibitory effect on prostaglandin biosynthesis resides virtually in the S-form. Interestingly, R-ketoprofen does not undergo substantial metabolic inversion in humans. Though contraindicated during the last trimester of pregnancy, NSAIDs, including ketoprofen, are used as tocolytic agents in some cases. The S/R plasma concentration ratio was reported to average 2.3 in premature neonates whose mothers were given rac-ketoprofen and to be close to 1 in the maternal plasma. Thus, we investigated the placental transfer of rac-ketoprofen in vitro using Schneider's perfused human cotyledon model. Glucosed Earle solutions with and without human serum albumin (HSA) were used. Several maternal perfusates were tested with different rac-ketoprofen concentrations together with 20 mg L-1 of antipyrine as a reference substance. Ketoprofen enantiomers were assayed by a specific HPLC method with derivatization procedure. HSA concentrations in maternal perfusate influenced the placental transfer of ketoprofen enantiomers. In the absence of HSA in the maternal perfusate, the S-(+)/R-(-) concentration ratio was close to 1 in the fetal perfusate. By contrast, this ratio averaged 1.44 after addition of HSA 10 g L-1 on the maternal side. Similar results were found for dialysis experiments using an inert Spectrapor 2 membrane suggesting that the S-(+)-free concentration is superior to the R-(-)-free concentration in the presence of HSA. Direct measurements of the free concentrations by centrifugal ultrafiltration confirmed this hypothesis. Accordingly, the data observed in vivo may result, at least in part, from the stereoselective protein binding of ketoprofen.

Clinical pharmacokinetics of ibuprofen. The first 30 years.

Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and methotrexate. A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated.

Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C

The cytochrome P450s responsible for the regio- and stereoselectivity in the 2- and 3-hydroxylation of the chiral non-steroidal antiinflammatory drug ibuprofen were characterized in human liver microsomes. The rates of formation of both the 2- and 3-hydroxy metabolites exhibited monophasic (N = 2; N is the number of microsomal preparations) and biphasic (N = 2) substrate concentration dependence for both enantiomers of ibuprofen. The high affinity enzyme class parameters for S-ibuprofen (N = 4) were: 2-hydroxylation, V max = 566 ± 213 pmol/min/mg, K m = 38 ± 13 μM; 3-hydroxylation, V max = 892 ± 630 pmol/min/mg, K m = 21 ± 6 μM. For R-ibuprofen, the corresponding parameters were: 2-hydroxylation, V max = 510 ± 117 pmol/min/mg, K m = 47 ± 20 μM; 3-hydroxylation, V max = 593 ± 113 pmol/min/mg, K m = 29 ± 8 μM. cDNA-expressed CYP2C9 (Arg 144 and Cys 144) favored S-2- and S-3-hydroxyibuprofen formation, but CYP2C8 favored R-2-hydroxyibuprofen formation. Sulfaphenazole, retinol, and arachidonic acid competitively inhibited the rate of formation of all hydroxyibuprofens; K i values (N = 3) for sulfaphenazole on the 2- and 3-hydroxylations of S-ibuprofen were 0.12 ± 0.05 and 0.07 ± 0.04 and of R-ibuprofen were 0.11 ± 0.07 and 0.06 ± 0.03 μM, respectively. Sulfaphenazole also competitively inhibited ibuprofen hydroxylation by cDNA-expressed CYP2C9 (Arg 144 and Cys 144) with K i values in the range of 0.05 to 0.18 μM and CYP2C8 in the range of 0.36 to 0.55 μM. In a bank of 14 human liver microsome samples, significant correlations ( r = 0.72 to 0.90; P < 0.01) were observed between the rates of formation of all four hydroxyibuprofens, and for each hydroxyibuprofen and prototypical CYP2C8/9 biotransformations. The regio- and stereoselectivities observed in vitro were consistent with those noted in vivo. The relative levels of both CYP2C8 and CYP2C9 and the expression of the corresponding variants may influence the disposition of ibuprofen in vivo.

Methods of analysis of chiral non-steroidal anti-inflammatory drugs.

Although the analysis of the enantiomers of chiral non-steroidal anti-inflammatory drugs (NSAIDs) has been carried out for over 20 years, there often remains a deficit within the pharmaceutical and medical sciences to address this issue. Hence, despite world-wide therapeutic use of chiral NSAIDs the importance of stereoselectivity in pharmacokinetic, pharmacodynamic and pharmacological activity and disposition has often been ignored. This review presents both the general principles that allow separation of chiral NSAID enantiomers, and discusses both the advantages and disadvantages of the available chromatographic assay methods and procedures used to separately quantify NSAID enantiomers in biological matrices.

Clinical pharmacokinetics of tiaprofenic acid and its enantiomers.

Tiaprofenic acid is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs is a sp3-hybridised tetrahedral chiral carbon heteroatom within the propionic acid side chain moiety, with the S-enantiomer possessing most of the beneficial anti-inflammatory activity. However, all tiaprofenic acid preparations to date are marketed as the racemate. Tiaprofenic acid has been suggested to exhibit limited pharmacokinetic stereoselectivity. The synovium is the proposed site of action of NSAIDs when used for musculoskeletal disorders, and substantial concentrations of tiaprofenic acid are attained in synovial fluid. Recent data suggested that possibility of stereoselective distribution of tiaprofenic acid into synovium and cartilage. Hence, data generated using non-stereospecific assays may not always be extrapolated to explain the disposition of the individual enantiomers. Tiaprofenic acid is rapidly and almost completely absorbed when given orally. The area under the plasma concentration-time curve (AUC) of tiaprofenic acid is proportional to the oral dose administered. A sustained release dosage form is available, which may be beneficial due to the short terminal phase half-life of tiaprofenic acid (3 to 6 hours). The bioavailability is the same as that with conventional rapid release preparations, although the peak plasma drug concentration is reduced and time peak is prolonged. Tiaprofenic acid binds extensively to plasma albumin. These is negligible R to S inversion upon oral administration. Tiaprofenic acid is eliminated following extensive biotransformation to glucuronide-conjugated metabolites. Approximately 60% is eliminated as conjugates excreted in urine, and little drug is eliminated unchanged. The rate of excretion of tiaprofenic acid and its conjugates may be related to renal function; accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Potentially clinically important drug interactions with tiaprofenic acid have been demonstrated for some anticoagulants and probenecid. Relationships between tiaprofenic acid concentrations in biological matrices and therapeutic or toxic effects have not yet been elucidated for this drug.

Effect of the Enantiomers of Flurbiprofen, Ibuprofen, and Ketoprofen on Intestinal Permeability

Numerous studies have demonstrated that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) increases small intestinal permeability, and this has been suggested to be a prerequisite to enteropathy. It is believed that the inhibitory effect of chiral NSAIDs on the synthesis of prostaglandins and hence their efficacy and toxicity are mainly due to the S enantiomer. Using the urinary excretion of [51Cr]-EDTA, we have investigated the effects of three nonsteroidal anti-inflammatory drugs (flurbiprofen, ibuprofen, and ketoprofen) on small intestinal permeability in rats. Single doses of each NSAID were administered orally as either the racemate or the R or S enantiomer, the enantiomer dose being half that of the racemate. Each treatment caused a significant increase in intestinal permeability above that seen in untreated animals. The R enantiomers of all three NSAIDs increased small intestinal permeability significantly above base line, which was expected for (R)-ketoprofen and (R)-ibuprofen due to substantial chiral R to S inversion. The intestinal permeability for (R)-flurbiprofen, although minimal and likely due to 10% inversion, may also suggest prostaglandin-independent involvement. Furthermore, (S)-flurbiprofen, used at one-half the dose of the racemate, increased permeability to a similar magnitude as the racemate. This observation was similar to that previously reported for etodolac. A stereochemically pure enantiomer does not necessarily offer a safer alternative than its racemic form.

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

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. 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. Plasma concentrations of the dextrorotatory (R) enantiomer (0.40 microgram/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. 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.

Chirality and nonsteroidal anti-inflammatory drugs.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are of significant clinical importance and include congeners of many chemical classes, some of which incorporate an asymmetric or chiral carbon atom. With very few exceptions, chiral NSAIDs have been marketed for clinical use as racemates. However, it is apparent that differences, sometimes major, exist between enantiomers in terms of their pharmacological and toxicological properties. With regard to the ability of chiral NSAIDs to inhibit cyclo-oxygenase, their chief mechanism of action, major or exclusive activity is confined to enantiomers of the S-stereoconfiguration. Accordingly, it is questionable whether the R-antipodes should be included in the final drug product for use in clinic. In addition to differences between enantiomers in terms of their pharmacodynamic properties, pharmacokinetic differences are possible for chiral NSAID isomers, and these may modulate preexisting enantioselectivities at the site of action of such compounds. As a consequence, a considerably simpler pharmacological profile is likely to result from the use of single enantiomers versus racemic mixtures.

Role of cytochrome P450 2C9 and an allelic variant in the 4′-hydroxylation of ( R)- and ( S)-flurbiprofen

Flurbiprofen is a chiral non-steroidal anti-inflammatory drug used in the treatment of pain or inflammation. The primary routes of biotransformation for ( R)- and ( S)-flurbiprofen are oxidation (presumably cytochrome P450) and conjugation. To date, the specific cytochrome P450 (P450) involved in the oxidative metabolism of this compound (specifically 4′-hydroxylation) has not been elucidated. Experiments were conducted to characterize the kinetic parameters ( K m and V max) for the 4′-hydroxylation of ( R)- and ( S)-flurbiprofen in human liver microsomes, to determine if enantiomeric interactions occur when both enantiomers are present, and to identify the specific P450 form(s) involved in this reaction. In human liver microsomes, the K m and V max(mean ± SD) for ( R)-4′-hydroxy-flurbiprofen formation were 3.1 ± 0.8 μM and 305 ± 168 pmol · min −1· mg protein) −1, respectively. In comparison, the K m and V max (mean ± SD) for( S)-4′-hydroxy-flurbiprofen formation were 1.9 ± 0.4 μM and 343 ± 196 pmol · min −1 · mg protein −1, respectively. Enantiomeric interaction studies revealed a decrease in K m and V max for both enantiomers and an apparent loss of stereoselectivity. Racemic-warfarin, tolbutamide, α-naphthoflavone and erythromycin were studied as potential inhibitors of this process. The estimated K i values for the inhibition of ( R)- and ( S)-4′-hydroxy-flurbiprofen formation by racemic-warfarin were 2.2 and 4.7 μM. This reaction was also inhibited by tolbutamide. In contrast, erythromycin and α-naphthoflavone had no appreciable effect on 4′-hydroxy-flurbiprofen formation. cDNA expression of individual forms was used to determine which P450 was involved in 4′-hydroxy-flurbiprofen formation. P450 2C9 and an allelic variant (R144C) readily catalyzed the formation of 4′-hydroxy-flurbiprofen. P450 1A2 was also active albeit with a turnover rate 1 140 th that of P450 2C9R144C (P450s 2C8, 2E1 and 3A4 were not active toward either enantiomer). The results of these studies indicate that the enantiomers of flurbiprofen may exhibit stereoselectivity with respect to enzyme affinity but have roughly equal maximum formation velocities. Additionally, these two enantiomers may compete for the enzyme resulting in lower maximum velocities for both enantiomers. Finally, of those P450 forms examined, only P450 2C9 and an allelic variant catalyzed the 4′-hydroxylation of both ( R)- and ( S)-flurbiprofen.

Clinical Pharmacokinetics of Flurbiprofen and its Enantiomers

Flurbiprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class. Although it possesses a chiral centre, with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity, both enantiomers may possess analgesic activity and all flurbiprofen preparations to date are marketed as the racemate. Flurbiprofen exhibits stereoselectivity in its pharmacokinetics. Stereoselectivity is exhibited at the level of protein binding and metabolite formation. Hence, the data generated using nonstereoselective assays may not be used to explain the pharmacokinetics of individual enantiomers. The absorption of flurbiprofen is rapid and almost complete when given orally. The area under the plasma concentration-time curve of flurbiprofen is proportional to the dose administered to patients. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase elimination half-life of conventional immediate release flurbiprofen (3 to 6 hours). They may also decrease local gastrointestinal adverse effects. Although with these preparations the peak plasma drug concentration is reduced and time taken to achieve peak concentrations is prolonged, the bioavailability is the same as that with regular release counterparts. Flurbiprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, which is the proposed site of action of NSAIDs. There is negligible R to S inversion after oral administration. Flurbiprofen is eliminated following extensive biotransformation to glucuro-conjugated metabolites. Conjugates are excreted in urine, and approximately 20% of flurbiprofen is eliminated unchanged. The excretion of conjugates may be tied to renal function as accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Although flurbiprofen is excreted into breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), coumarins and propranolol. The relationship between concentration and anti-inflammatory and analgesic effect has yet to be elucidated for this drug.

Rationale for the Development of Stereochemically Pure Enantiomers: Are the R Enantiomers of Chiral Nonsteroidal Anti-Inflammatory Drugs Inactive?

Rationale for the Development of Stereochemically Pure Enantiomers: Are the R Enantiomers of Chiral Nonsteroidal Anti-Inflammatory Drugs Inactive?

Etodolac clinical pharmacokinetics.

Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marked as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain. Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. In plasma, the concentrations of the 'inactive' R-enantiomer are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. In common with other NSAIDs, the drug is highly plasma protein bound, and undergoes virtually complete biotransformation to oxidised metabolites and acyl-glucuronides. Etodolac is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic etodolac increases linearly with doses used clinically. The elimination half-life of etodolac is between 6 and 8 hours in plasma, and is similar for both enantiomers. The volume of distribution (Vd) of racemic etodolac is higher than that of most other NSAIDs mainly because of the extensive distribution of the S-enantiomer. The very large Vd of the S-enantiomer, compared with its antipode is, at least in part, due to its less extensive plasma protein binding. In addition to the unchanged drug, substantial concentrations of the acyl-glucuronides of etodolac are found in both plasma and the synovial fluid of patients with arthritis. A limited amount of conjugated etodolac is found in the bile of patients following cholecystectomy. Hepatic cirrhosis has no effect on the pharmacokinetics of racemic etodolac, although the effect of hepatic dysfunction on the pharmacokinetics of the individual enantiomers has yet to be determined. In elderly non-arthritic individuals with excellent kidney function, aging does not affect the pharmacokinetics of etodolac. The pharmacokinetics of the drug in patients with renal failure have not been published, and may be important because the acyl-glucuronides are renally cleared.

Limited extent of stereochemical conversion of chiral non-steroidal anti-inflammatory drugs induced by derivatization methods employing ethyl chloroformate

A potential problem with chiral derivatization is the possibility of stereochemical conversion during the derivatization reaction. This possibility has been examined using the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen, etodolac and flurbiprofen. To avoid possible interference from stereochemical impurities, male Sprague—Dawley rats were dosed intraperitoneally with the S enantiomer (100 mg/kg) of each drug and the R enantiomer of etodolac. Blood samples were taken 4 h afterwards. The plasma samples were analyzed using published stereospecific methods involving chiral derivatization with ethyl chloroformate followed by either R-(+)-α-phenylethylamine or l-leucinamide. For all the drugs examined, the percentage of formation of the antipode was between 1.0 and 5.8%. In vitro studies of the R and S enantiomers demonstrate that the apparent extent of conversion is inversely related to the concentration of ethyl chloroformate present during the derivatization reaction for ibuprofen, ketoprofen and flurbiprofen but not for etodolac. However, both the R and S enantiomers appear to be inverted to the same extent in the presence of ethyl chloroformate. These results suggest that the degree of stereochemical conversion induced by these assay procedures is small and would not contribute significantly to analytical error in the absence of a large difference in concentrations of the enantiomers.

Ketoprofen-Probenecid Interaction in the Rat: A Probenecid Concentration-Dependent Stereoselective Process

Probenecid (PB) is believed to interact with the chiral nonsteroidal anti-inflammatory drug ketoprofen (KT) through competition for glucuronide conjugation and subsequent renal and/or biliary excretion of formed KT conjugates. It is unknown whether the interaction is dependent on PB concentration and whether both KT enantiomers are affected to the same extent. We measured intact and conjugated R-KT, S-KT, and PB in the plasma and urine of female Sprague-Dawley rats after intravenous doses of 10mg of racemic KT per kg and 0,25,50,100, 150,175, and 200mg of PB per kg. Elevated levels of both enantiomers were observed, with S-KT being affected to a much greater extent. Significant positive correlations were found between the concentrations in plasma of KT enantiomers and PB at various sampling times, with the strongest correlations being found at 2h for R-KT (r = 0.708) and 1.5h for S-KT (r = 0.913). The areas under the concentration-time curve (AUC) from 0-24h for R-KT (r = 0.697) and S-KT (r = 0.848) also showed strong correlation with AUC of PB. Our data show that as the dose of PB was increased (0-200mg/kg), the mean S-KT/R-KT ratios for both the AUC and the fraction of the dose excreted as enantiomer conjugates in urine over 24h increased progressively from 12.1 ± 2.3 to 27.6 ± 5.0 and from 6.8 ± 0.7 to 36.4 ± 12.2, respectively. These findings clearly demonstrate that the KT-PB interaction in the rat is a PB concentration-dependent process. The importance of considering stereochemistry in evaluating potential drug interactions is also highlighted.

Clinical pharmacokinetics of ketorolac tromethamine.

Ketorolac is a new chiral nonsteroidal anti-inflammatory drug (NSAID) which is marketed for analgesia as the racemate. The drug is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular injection. The absorption of ketorolac is rapid, Cmax being attained between 20 to 60 min. Its oral bioavailability is estimated to range from 80 to 100%. The drug is extensively bound (> 99%) to plasma proteins and has a volume of distribution (0.1 to 0.3 L/kg) comparable with those of other NSAIDs. Only small concentrations of ketorolac are detectable in umbilical vein blood after administration to women in labour. The elimination half-life is between 4 and 6h and is moderate in comparison with other NSAIDs. The area under the plasma concentration-time curve of ketorolac is proportional to the dose after intramuscular administration of therapeutic doses to young healthy volunteers. Ketorolac is extensively metabolised through glucuronidation and oxidation; little if any drug is eliminated unchanged. Most of the dose of ketorolac is recovered in the urine as conjugated drug. Although ketorolac is excreted into the breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Little stereoselectivity was present in the pharmacokinetics of ketorolac in a healthy volunteer receiving single intravenous or oral doses. The elderly exhibit reduced clearance of the drug. Renal insufficiency appears to cause an accumulation of ketorolac in plasma, although hepatic disease may not affect the pharmacokinetics.

Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs.

Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs.