The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans

Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)-enantiomer. However, a portion of R(-)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)-enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(-)-ibuprofen which was metabolically inverted to S(+)-ibuprofen, was independent of the administered dose.     

Lack of effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen.

1. To investigate the effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug-free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross-over manner. 2. The plasma concentrations of R(-)- and S(+)-ibuprofen were measured by high-performance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3. There was no difference (P greater than 0.05, two-tailed Student's t-test; data expressed as mean +/- s.d.) between C and T phases in the total area under the plasma concentration-time curve of R(-)-ibuprofen (C 4514 +/- 1063 mg 1(-1) min vs T 4665 +/- 1435 mg 1(-1) min) and S(+)-ibuprofen (C 6460 +/- 1063 mg 1(-1) min vs T 6886 +/- 1207 mg 1(-1) min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half-life, the maximum plasma concentration or the time of its occurrence. 4. Cimetidine treatment had no effect (P greater than 0.05) on the time-averaged percent unbound in plasma of R(-)-ibuprofen (C 0.419 +/- 0.051% vs T 0.435 +/- 0.060%) and S(+)-ibuprofen (C 0.643 +/- 0.093% vs T 0.633 +/- 0.053%). (ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.

1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51-79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min-1. 2. The fractions unbound of (R)- and (S)-ketoprofen in plasma were determined for each subject after in vitro addition of rac-ketoprofen (enantiomer range: 1.00-6.00 micrograms ml-1) to pre-dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre-dose) spiked with rac-ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)-ketoprofen and CLCR. Corresponding relationships were also observed for the (R)-enantiomer of ketoprofen. In addition, the half-life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non-conjugated and conjugated (R)-ketoprofen and CLCR while that for the (S)-stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)- and (S)-ketoprofen for either unbound or total drug. 6. The mean +/- s.d. percentage unbound of (S)-ketoprofen in plasma (0.801 +/- 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/- 0.149%). The percentage unbound of the (S)-enantiomer was higher at 6.00 micrograms ml-1 than that at enantiomer concentrations of 3.50 micrograms ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 micrograms ml-1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)-ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/- s.d. EC50 was 0.216 +/- 0.143 ng ml-1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)-ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl-glucuronide conjugates. The apparent sensitivity of platelet cyclo-oxygenase to the inhibitory effect of (S)-ketoprofen was not influenced by renal function.     

The effect of competitive and non-linear plasma protein binding on the stereoselective disposition and metabolic inversion of ibuprofen in healthy subjects

The stereoselective disposition and metabolic inversion of ibuprofen were studied in 12 healthy subjects under conditions of competitive and non-linear plasma protein binding. Each subject received each of four oral treatments according to a Latin-square design: 300 mg R(?)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(?)- + 300mg S(+)-ibuprofen, and 300 mg R(?)- + 600 mg S(+)-ibuprofen. For a given treatment, the partial clearance of S(+)-ibuprofen was greater than that of R(?)-ibuprofen for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)-ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(?)-ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances of R(?)- and S(+)-ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largely due to ibuprofen's non-linear binding.     

Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin.

A series of nonsteroidal anti-inflammatory drugs (NSAIDs) [S(+)-naproxen, ibuprofen isomers, and indomethacin] were evaluated for their activation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms in CV-1 cells co-transfected with rat PPAR alpha and gamma, and peroxisome proliferator response element (PPRE)-luciferase reporter gene plasmids, for stimulation of peroxisomal fatty acyl CoA beta-oxidase activity in H4IIEC3 cells, and for comparative inhibition of ovine prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2 and arachidonic acid-induced human platelet activation. Each drug produced a concentration-dependent activation of the PPAR isoforms and fatty acid beta-oxidase activity, inhibition of human arachidonic acid-induced platelet aggregation and serotonin secretion, and inhibition of PGHS-1 and PGHS-2 activities. For PPARalpha activation in CV-1 and H4IIEC3 cells, and the stimulation of fatty acyl oxidase activity in H4IIEC3 cells, the rank order of stereoselectivity was S(+)- ibuprofen > R(-)-ibuprofen; S(+)-ibuprofen was more potent than indomethacin and naproxen on these parameters. On PPARgamma, the rank order was S(+)-naproxen > indomethacin > S(+)-ibuprofen > R(-)-ibuprofen. Each drug inhibited PGHS-1 activity and platelet aggregation with the same rank order of indomethacin > S(+)-ibuprofen > S(+)-naproxen > R(-)-ibuprofen. Notably, the S(+)-isomer of ibuprofen was 32-, 41-, and 96-fold more potent than the R(-)-isomer for the inhibition of PGHS-1 activity, human platelet aggregation, and serotonin secretion, respectively. On PGHS-2, the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen, and S(+)-naproxen were 6-, 27-, and 5-fold more potent as inhibitors of PGHS-1 than PGHS-2 activity. These results demonstrate that the mechanisms of action of NSAIDs on these cell systems are different, and we propose that the pharmacological effects of NSAIDs may be related to both their profile of inhibition of PGHS enzymes and the activation of PPARalpha and/or PPARgamma isoforms.     

Pharmacokinetics of S(+)- and R(−)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis

Summary S(+)-, R(−)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(−)- and 600 mg racemic ibuprofen. The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(−)-ibuprofen, whereas R(−)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(−)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(−)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer. Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested. Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.     

Stereoselective plasma protein binding of ibuprofen enantiomers

Summary We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis.We have determined the plasma protein binding of R(–)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen.The mean time-averaged percentage unbound of the R(–)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding.The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.     

Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p < 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2'R, 2R)- and (2'S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.     

Stereoselective,competitive, and nonlinear plasma protein binding of ibuprofen enantiomers as determinedin vivo in healthy subjects

The plasma protein binding and competitive inhibition parameters of R(–)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4×4 Latin square design in which oral solutions of drug were administered as 300 mg R (–)-ibuprofen, 300 mg S (+)-ibuprofen, 300 mg R (–)-+300 mg S (+)-ibuprofen, and 300 mg R(–)-+600 mg S (+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled¹⁴C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was Stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2=0.358±0.185 vs. SP2=0.979 ±0.501 g/ml; X±SD) but no differences in their binding capacity (RP1=160±86 vs. SP1=161 ±63 g/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI=0.661 ±0.363 vs. RKI=0.436 ±0.210 g/ml). As a result, the intrinsic binding (i.e.), P1/P2J of R(–)-ibuprofen was greater than S(±)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.This work was supported in part by a grant from The Upjohn Company, and by grants R01 GM 35498 and MO1 RR00042 from the National Institutes of Health. During the course of this work, J. K. Paliwal was supported by a CONRAD Fellowship.     

Equipotent inhibition by R(-)-, S(+)- and racemic ibuprofen of human polymorphonuclear cell function in vitro.

1. The effects of racemic (rac) ibuprofen and its S(+)- and R(-)-enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac-ibuprofen inhibited PMN functions (O2- generation, beta-glucuronidase release, LTB4 formation). Similar IC50 values (40-100 microM) were obtained for the S(+)- and R(-)-enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase-related platelet functions (aggregation, thromboxane formation). The S(+)-enantiomer was about twice as active as the racemate while the R(-)-enantiomer was at least 10-fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac-ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(-)-ibuprofen may be superior to the S(+)-isomer for the treatment of PMN-dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.     

A comparative study of the pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers

OBJECTIVE: Ibuprofen arginate is a salt formulation of ibuprofen designed to reach target concentrations rapidly. The primary objective of this study was to compare the 12-h pharmacokinetic profile of S(+)-ibuprofen following administration of single doses of ibuprofen arginate (600 mg) and dexibuprofen (400 mg) in healthy volunteers. METHODS: Twenty-four volunteers were recruited into an open-label, randomised, two-period, single-centre study with crossover design. RESULTS: Both treatments were well tolerated. Ibuprofen arginate and dexibuprofen showed similar bioavailability for S(+)-ibuprofen. Compared with dexibuprofen, ibuprofen arginate demonstrated a 45% higher maximum concentration (C(max)), and a time to peak concentration (T(max)) 2 h sooner. CONCLUSION: Ibuprofen arginate approaches maximum concentrations of S(+)-ibuprofen faster and higher than dexibuprofen.     

Pharmacokinetic interaction of ibuprofen enantiomers in rabbits

The potential interaction between two ibuprofen enantiomers was studied after intravenous administration of R-(-)-, S-(+)- and racemic ibuprofen to rabbits. The total body clearance values calculated by compartmental model analysis (0.65 +/- 0.21 for R-(-)-ibuprofen and 0.63 +/- 0.34 for S-(+)-ibuprofen) after intravenous administration of the racemate of ibuprofen were significantly smaller than those of individual enantiomers (0.95 +/- 0.23 for R-(-)-ibuprofen and 1.03 +/- 0.23 for S-(+)-ibuprofen), indicating that the enantiomer-enantiomer interaction results in a mutual inhibition. The enantiomeric interaction in the pharmacokinetic behaviour of ibuprofen after racemic administration is considered to be a result of an alteration in the metabolic or excretion phase (or both) rather than stereoselective protein binding in the systemic distribution.     

The site of inversion of R(-)-ibuprofen: studies using rat in-situ isolated perfused intestine/liver preparations.

The site of metabolic inversion of R(-)-ibuprofen to the pharmacologically active S(+)-enantiomer has been investigated using an array of in-situ rat perfused organ preparations allowing vascular perfusion (55-60 min) of the separate or combined intestine and liver. After addition of R(-)-ibuprofen (20 mg kg-1 body weight) to the closed (static) lumen of isolated 25 cm lengths of duodenum, jejunum or ileum, and single-pass vascular perfusion, both isomers were measured in the lumen and in vascular perfusate plasma (mean plasma AUC values (+/- s.d., micrograms mL-1 min, n = 5) R(-)-ibuprofen: 1669 +/- 115 (duodenum), 1687 +/- 203 (jejunum), 2061 +/- 188 (ileum); S(+)-ibuprofen: 23 +/- 6 (duodenum), 14 +/- 5 (jejunum), 26 +/- 1 (ileum]. Addition of the same dose of S(+)-ibuprofen to the jejunum (n = 5) resulted in AUC values of 1864 +/- 238 for S(+)-ibuprofen and 6 +/- 3 for R(-)-ibuprofen. After addition of R(-)-ibuprofen (30 micrograms mL-1) to the recirculating vascular perfusate (100 mL) of the entire small intestine (n = 6) AUC values were 1647 +/- 34 for R(-)-ibuprofen and 13 +/- 3 for S(-)-ibuprofen. The same dose of R(-)-ibuprofen to combined intestine/liver (n = 6) and liver only preparations (n = 6) gave AUC values of 1011 +/- 25 and 1021 +/- 49 for R(-)-ibuprofen and 220 +/- 28 and 238 +/- 22 for S(+)-ibuprofen, respectively. In all experiments, except those involving perfusion of the combined intestine/liver and the liver, the concentrations of the isomer opposite to that administered could be accounted for solely by the level of enantiomeric impurity (1.3% for R(-)-ibuprofen and 0.6% for S(+)-ibuprofen). We conclude that inversion of R(-)-ibuprofen to the S(+) antipode occurs in the liver but does not occur on either mucosal or serosal sides of the small intestine of the rat.     

Pharmacokinetics of the enantiomers of ibuprofen in the rabbit.

The stereoselective disposition of ibuprofen was studied in male New Zealand White (NZW) rabbits (n = 4) following an infusion (0.16 mg/kg/min) to steady-state of each of the enantiomers of ibuprofen with one week between treatments. The mean (+/- SEM) steady-state clearances of (R)-ibuprofen (15.5 +/- 1.1 ml/min/kg) and (S)-ibuprofen (13.6 +/- 1.9 ml/min/kg) were not significantly different from each other (p greater than 0.05) and exceeded the plasma clearance of indocyanine green (4.3 +/- 0.4 ml/min/kg) in a separate group of rabbits (n = 6). When the infusion rate of the enantiomers was doubled there was a significant decrease in the mean clearance of both (R)-ibuprofen (28%; p less than 0.018) and (S)-ibuprofen (24%; p less than 0.003). There was enantiospecific chiral inversion of (R)-ibuprofen to (S)-ibuprofen (fi = 0.30 +/- 0.07) as has been observed in all species so far studied for this 2-arylpropionic acid. The metabolic capacity for elimination of ibuprofen enantiomers was much greater than reported for either fenoprofen or ketoprofen and suggests that the clearance of ibuprofen enantiomers may be flow dependent in this species.     

Chiral separation of ibuprofen and chiral pharmacokinetics in healthy Chinese volunteers.

A rapid, sensitive and stereoselective HPLC method based on chiral column analysis was developed and fully validated for the simultaneous determination of the two enantiomers of ibuprofen in human plasma. Using this method, a chiral pharmacokinetic study of two different ibuprofen tablets, i.e. dexibuprofen tablets and racemic ibuprofen tablets, was carried out on 20 healthy Chinese male volunteers according to a single-dose (400 mg), two-way, cross-over randomized design. When a 'non-chiral calculation method' was used, the statistical analysis showed no significant difference for the pharmacokinetic parameters (AUC0-infinity, AUC0-t, Cmax and tmax) between the two oral formulations, suggesting that they were pharmaceutically bioequivalent. Considering that the pharmacological activity of ibuprofen resides exclusively in the S(+)-enantiomer, and that the unidirectional inversion of the R(-) to the S(+)-enantiomer is incomplete and might be race-dependent, the pharmacokinetic parameters for only the S(+)-enantiomer were further compared and the inversion ratio calculated. It was found that only 25% of R(-)-ibuprofen in the racemic ibuprofen tablets was inverted into S(+)-ibuprofen in the Chinese population, which suggested that dexibuprofen might possess a much stronger pharmacological activity than that of racemic ibuprofen when administered at the same dose.     

布洛芬离体肝代谢中对映体间的相互作用

目的研究布洛芬离体肝代谢中对映体之间的相互作用。方法用家兔肝匀浆质与单纯的R(- ) 或S(+) 布洛芬以及两对映体以不同比例的混合物 ,加入必要的辅助因子进行离体肝手性转化代谢试验 ,利用立体选择性HPLC法测定各对映体以及中间产物硫酯的质量浓度。结果布洛芬手性转化代谢由R(- ) 型向S(+) 型单向进行 ,在S(+) 布洛芬的存在下 ,R(- ) 布洛芬的转化量减少 ,中间产物硫酯的生成量减少。结论S(+) 布洛芬在一定程度上抑制手性转化的进行     

Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400?mg) to 12 healthy volunteers. 2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S) -ibuprofen was significantly greater than that of the R -enantiomer (74.5 ± 18.1 versus 57.1 ± 11.7 ml?min -1 ; p < 0.05) and the clearance of (R) -ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 ± 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R) -ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S) -ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively. 6. Modest stereoselectivity was observed in the formation of (2' R, 2 R) - and (2' S, 2 S) -carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.     

Antiarrhythmic activity and unbound concentrations of disopyramide enantiomers in patients

Six patients with reproducible inducible atrial flutter randomly received, in double-blinded fashion, 77 mg of S(+)-disopyramide and R(-)-disopyramide over 20 min by intravenous infusion on two occasions separated by at least 24 h. The S(+) enantiomer prevented the inducibility of atrial flutter in five of the six patients; atrial flutter was inducible following R(-) enantiomer administration in all six patients (p less than 0.05). The mean (+/- SD) antiarrhythmic unbound serum concentration range of S(+)-disopyramide was 0.55 +/- 0.31-0.90 +/- 0.81 mg/L. The binding of disopyramide was stereoselective: the mean unbound fractions of S(+)- and R(-)-disopyramide were 0.207 +/- 0.119 and 0.338 +/- 0.214 (p less than 0.05). Binding of the individual enantiomers in some patients was markedly concentration dependent. The data suggest that the antiarrhythmic activity associated with racemic disopyramide resides in the S(+) enantiomer.     

Studies on the metabolism and chiral inversion of ibuprofen in isolated rat hepatocytes

The oxidative metabolism and chiral inversion of ibuprofen in freshly isolated rat hepatocytes was studied with the aid of a stereoselective GC/MS assay procedure. Hydroxylation of the isobutyl side chain at the subterminal carbon (to give hydroxyibuprofen) proved to be the major route of metabolism of both R(-)-ibuprofen and S(+)-ibuprofen, while formation of the corresponding diastereoisomeric 2-methylpropionic acid derivatives (carboxyibuprofen) was of minor quantitative importance. Both oxidative pathways were inhibited in the presence of metyrapone, a cytochrome P-450 inhibitor. R(-)-Ibuprofen underwent metabolic chiral inversion to the S(+) enantiomer, whose formation was dependent on incubation time, cell density, and substrate concentration. S(+)-Ibuprofen, on the other hand, was not converted to R(-)-ibuprofen in rat hepatocytes. When cells were incubated with a mixture of unlabeled R(-)-ibuprofen and R(-)-[3,3,3-2H3]ibuprofen, the resultant S(+) enantiomer consisted only of unlabeled and trideutero molecules (formed in the same ratio as the corresponding species of R(-)-ibuprofen), indicating that 2,3-dehydroibuprofen did not serve as the symmetrical intermediate in the chiral inversion reaction. Collectively, these results demonstrate that freshly isolated rat hepatocytes represent a convenient and reproducible in vitro model system for studies on the metabolism and chiral inversion of ibuprofen.     

Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen

Two bioavailability studies of S(+)-ibuprofen (dexibuprofen) were conducted in healthy volunteers to define the relationship between the bioavailability of the drug after administration of dexibuprofen alone or as part of ibuprofen racemate. Enantioselective plasma drug analysis was used throughout. In the first study, the bioavailability of dexibuprofen from a 400 mg tablet formulation was compared with that from 400 mg in aqueous solution.The tablet formulation did not influence the bioavailability of the drug and dexibuprofen was well absorbed from the gastro-intestinal tract.The second study was divided into three identical parts. Bioavailability of dexibuprofen 200, 400 and 600 mg was compared with its bioavailability from ibuprofen racemate 400, 800 and 1200 mg.The second study showed that the mean relative bioavailability of dexibuprofen to ibuprofen racemate was 0.66, thus enabling the estimation of clinically useful dexibuprofen doses from the usual doses of the racemate. The 95% confidence interval limits did not include 0.5, leading to the conclusion that administering half of the racemate dose would not provide patients with an adequate amount of therapeutically active drug.