Pharmacokinetics of ibuprofen enantiomers in children with cystic fibrosis

Chiral inversion of R(-)- to S(+)-ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2-13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean Cmax, AUC, apparent CL/F, and Varea/F of S-ibuprofen were significantly different from those of R-ibuprofen. The enantiomeric ratio of plasma AUC (S:R = 2.09:1) and of free and conjugated ibuprofen in urine (S:R = 13.9:1) of children with cystic fibrosis was not different from reported values for healthy children and adults. No significant gender difference was observed for any of the pharmacokinetic parameters determined. However, there was an inverse linear relationship between the CL/F of R-ibuprofen and age in children with cystic fibrosis. Apparent CL/F was higher in children with cystic fibrosis than previously reported for healthy children; therefore, higher doses of ibuprofen would be necessary for children with cystic fibrosis.     

Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man.

The pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 x 400 mg doses of Nurofen were determined in 12 healthy volunteers. Terminal half-lives were similar for both enantiomers, but plasma levels of S-ibuprofen were higher than those of R-ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time-dependency. A large inter-individual variability in the ratio of S- to R-ibuprofen average concentrations at steady-state was observed (mean +/- SD 1.89 +/- 0.89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.     

布洛芬精氨酸注射及口服给药在大鼠体内的立体选择性药代动力学

利用手性高效液相色谱法研究大鼠注射及口服布洛芬精氨酸之后布洛芬对映体的药代动力学。布洛芬精氨酸注射及口服给药后, 布洛芬对映体的药代动力学呈现立体选择性, 且口服给药后立体选择性程度更高。与系统前转化相比, R-布洛芬至S-布洛芬的系统转化在口服给药后立体选择性药代动力学中起更重要的作用。布洛芬精氨酸口服给药后, 优势对映体S-布洛芬迅速吸收, S-布洛芬与R-布洛芬的绝对生物利用度分别为100% 和80%。基于研究发现的S-布洛芬体内系统性暴露, 可以推断布洛芬精氨酸注射及口服给药后的药理作用相似, 仅在作用的起始阶段存在差异。     

Stereoselective disposition of ibuprofen enantiomers in man.

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.     

Variability in the disposition of ibuprofen enantiomers in osteoarthritis patients.

The pharmacokinetics of the enantiomers of ibuprofen have been investigated following oral administration of 300 or 600 mg of racemic ibuprofen four times daily to 45 patients with osteoarthritis. Fifteen of these patients also received single doses of 300 or 600 mg of racemic ibuprofen. Serum concentrations of R- and S-ibuprofen and urine concentrations of the stereoisomers of ibuprofen and its metabolites were measured by high-performance liquid chromatography. The fraction inverted (F(inv)) of the inactive R- to active S-ibuprofen was estimated by a urinary metabolite method. For the 15 patients in both the chronic and single dose studies, there were no significant differences in the clearance of R-ibuprofen or F(inv). The elimination half-lives of R- and S-ibuprofen were comparable for the single and chronic dosing studies. The area under the curve (AUC) values, 6-h trough concentrations, and average steady state concentrations of the R- and S-enantiomers were statistically different after chronic dosing. Despite considerable variability in the clearances in these patients, e.g., clearance (CL) of R-ibuprofen showed 28-49% CV, much less variability was seen in F(inv) (range 9-19% CV), implying that patients would receive similar effective doses of active S-ibuprofen in spite of large differences in kinetics.     

Pharmacokinetics of sotalol enantiomers in humans.

The chiral beta-blocker, sotalol (STL), is marketed as a racemic mixture. Although both STL enantiomers have equal Class III antiarrhythmic activity, beta-blocking activity has been ascribed mainly to the R-enantiomer. The pharmacokinetics of STL enantiomers were studied in young (mean age 32 +/- 3 years), healthy male volunteers after oral administration of 160 mg. Subsequent plasma and urine samples were collected over 24 hours, and STL enantiomer concentrations were determined using a stereospecific high-performance liquid chromatography assay. There were no significant differences between pharmacokinetic parameters of enantiomers. The area under the time-concentration curves (mean +/- standard deviation [SD]) were 6.95 +/- 0.85 and 6.76 +/- 1.2 (mg/L)hour for S- and R-STL, respectively. Maximal plasma concentrations of S- and R-STL were 615 +/- 167 and 619 +/- 164 ng/mL, respectively, which were obtained on average, 3.13 +/- 0.60 hours after dosing. The mean residence time (mean +/- SD) was 13.2 +/- 1.2 and 12.9 +/- 1.8 hours for S- and R-STL, respectively. Respective renal clearance values for S- and R-STL were 8.98 +/- 1.5 and 9.46 +/- 2.3 L/hour, and were approximately 1.5 times greater than creatinine clearance. Renal clearance constituted approximately 76% of the oral clearance. Although stereoselective disposition of STL was absent after racemate administration, these results should not be extrapolated to patients with significantly altered physiology, or to the pharmacokinetics of S-STL after administration of pure-S-STL.     

Pharmacokinetics of acebutolol enantiomers in humans.

The chiral beta-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major metabolite, diacetotol (DC), are chiral, the S-enantiomer possessing beta-blocking activity. The pharmacokinetics of AC and DC enantiomers was determined in 12 healthy subjects following oral administration of 200 mg of AC. Plasma and urine were collected over a 24-hr period and both AC and DC enantiomers were measured utilizing a stereospecific HPLC assay. Concentrations of S-AC were predominant in both plasma and urine [AUC S:R, 1.20 +/- 0.1; cumulative urinary excretion (sigma Xu) S:R, 1.17 +/- 0.05), which corresponded to a significantly greater oral clearance of R-AC (106 +/- 30 L/h) than S-AC (87 +/- 22 L/h). The Cmax of R-DC was significantly greater than for S-DC (S/R 0.7 +/- 0.1). The half-life (t1/2) of R-DC (6.4 +/- 1.6 h) was significantly shorter than that of S-DC (8.8 +/- 2.4 h). The observed AUC values for R- and S-DC were not significantly different. Renal clearance of R-DC (70 +/- 34 mL/min) was significantly greater than that of S-DC (53 +/- 29 mL/min). The data suggest that the first-pass metabolism of R-AC to R-DC is stereoselective. This metabolism, coupled with the stereoselective renal excretion of R-DC is likely a major contributor to the observed stereoselective disposition of AC and its major metabolite in humans.     

Monitoring ibuprofen enantiomers released from polymeric systems.

Two methacrylic derivatives of ibuprofen (N-[4-[2-(4-isobutylphenyl)propionyloxy]phenyl] methacrylamide (MAI) and 2-[(4-isobutylphenyl)propionyloxy]ethyl methacrylate (MEI)) were used together with 2-hydroxyethyl methacrylate (HEMA) to synthesize four polymeric materials: two hydrophobic homopolymers, PMAI and PMEI, and two hydrophilic copolymers containing 70% (w/w) HEMA, MAI-HEMA 30 and MEI-HEMA 30. The enantiomeric determination of R- and S-IBU released from these four systems has been carried out by capillary electrophoresis. Release of R- and S-IBU was monitored during in vitro assays done at 37 degrees C at pH 7.4 and 10 in buffered solutions and rat plasma. There is a hydrolytical activation in plasma and at pH 10 compared to pH 7.4; moreover, the release rate from the copolymers is much higher than from the homopolymers as a consequence of the greater hydrophilic character. A slight excess of the S-enantiomer of IBU is observed in all the experiments, being more relevant at higher release rates, i.e. copolymers at pH 10.     

Pharmacokinetics of the enantiomers of acenocoumarol in man.

1 The pharmacokinetics of R(+)-, S(-)- and R,S(+/-)-acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(-). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(-) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half-life of S(-) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume of distribution VdSS of S(-) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(-) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.     

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Since both (R)- and (S)-enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve-root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac-ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half-lives of (R)- and (S)-ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)- and (S)-forms, respectively.     

Stereoselective disposition of ibuprofen enantiomers in infants

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 ± 0.3 mg kg^-1 dose of the racemate in 11 infants. Mean (± s.d.) half-lives were 1.6 ± 0.5 h for S(+) and 1.5 ± 0.5 h for R(-) and mean (± s.d.) AUC values were 31.5 ± 14.3 mg l^-1 h for S(+) and 36.6 ± 13.8 mg l^-1 h for R(-). Since plasma concentrations of the active S(+)-isomer were lower than those reported in adults, a higher dosage might be required in infants.     

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.     

Pharmacokinetics of the warfarin enantiomers in rats

The pharmacokinetics of elimination and anticoagulant action of the R(+) and S(-) enantiomers of warfarin were determined in individual adult male Sprague- Dawley rats. A 12 mg/kg dose of one of the enantiomers and a tracer dose of racemic ¹⁴C -warfarin were injected intravenously, and the same doses of the other enantiomer and the tracer were administered 3 weeks later to the same animals. The apparent biological half- life of racemic warfarin ranged from about 6 to 18 hr and was very reproducible in individual animals. The ranges of the biological half-lives of R(+) and S(-)-warfarin were 4.9–9.6 hr and 7.7–21.6hr, respectively. There is a strong positive correlation between the half- life of each enantiomer in individual rats; the ratio of these half- lives, S(-):R(+), is 1.87 (sd 0.21, n=10). The apparent half- life of racemic warfarin in individual rats is in very good agreement with the half- life predicted from the sum of the plasma concentrations of R(+)-andS(–)-warfarin at various times after injection. There was no significant difference in the apparent volumes of distribution of R(+)-,S(-)-, and racemic warfarin. There was a pronounced intersubject variation in the relative potency of the two enantiomers; the ratio R(+):S(-) of the plasma concentrations required to decrease the synthesis rate of prothrombin complex activity by one-half ranged from 0.7 to 6.3, with a mean of 2.2.Supported by grant GM20852 from the National Institute of General Medical Sciences, National Institutes of Health.This is paper XII in the series Comparative Pharmacokinetics of Coumarin Anticoagulants. Previous paper: G. Levy and A. Yacobi,J. Pharm. Sci. 63: 805–806, 1974.     

Pharmacokinetics of ticlopidine in the rabbit.

There is no information about the pharmacokinetics of ticlopidine in rabbits. Such information is valuable in designing appropriate dosing regimens for experimental studies of the drug with ultimate applications in man. The disposition kinetics of ticlopidine at three dose levels were evaluated in three groups of six rabbits which received 10, 50 or 100 mgkg(-1) drug once daily via the oral-gastric route. Blood samples were collected at predetermined times after the third dose. Plasma concentrations of the unchanged drug were determined by a validated liquid chromatography-mass spectrometry method with a limit of detection of 5 microg L(-1). There was a disproportionate increase in the mean maximum plasma concentration (Cmax) and the area under the plasma drug-concentration-time curve (AUC) for the 10 and 50 mgkg(-1) doses. The apparent terminal half-life (t1/2beta), apparent volume of distribution (Vdbeta/F), and total plasma clearance (CLp/F) of the drug were all dose-dependent. For example, t1/1beta for the 10, 50 and 100 mgkg(-1) doses were 1.04+/-0.10, 4+/-24+/-1.92 and 12.80+/-6.35 h, respectively, whereas the Vdbeta/F values for the corresponding doses were 214 31, 475 221 and 998+/-420 Lkg(-1), respectively. These results show that the 100-mgkg(-1) dose produces plasma ticlopidine concentrations similar to those found in man after administration of 250 mg of the drug. It is suggested that 100 mg kg(-1) might be the appropriate dose of ticlopidine for use in rabbit experimental studies with ultimate application to man.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

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.