Disposition of flurbiprofen in man: influence of stereochemistry and age

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4'-hydroxy- metabolite in serum and the drug, 4'-hydroxy- and 3'-hydroxy-4'-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4'-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4'-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p<0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.     

Stereoselective disposition of flurbiprofen in normal volunteers.

1. The concentrations of the R- and S-enantiomers of flurbiprofen and its metabolites were measured in plasma and urine following the oral administration of 50 mg racemic flurbiprofen to six normal volunteers. 2. The AUC and half-life of the R-enantiomer were significantly lower than the corresponding S-enantiomer values reflecting the greater clearance of R-flurbiprofen (20.42 +/- 4.71 vs 16.12 +/- 3.60 ml min-1). 3. Ex vivo protein binding studies indicated that the percent unbound of R-flurbiprofen was (not significantly) greater than that of the S-enantiomer (0.055 +/- 0.008 vs 0.049 +/- 0.009) and the corresponding unbound clearances did not show enantioselectivity. 4. Both enantiomers were cleared primarily by metabolism to an acylglucuronide and 4'-hydroxyflurbiprofen. There was significant enantioselectivity (R greater than S) in the formation clearances of these metabolites which remained when unbound metabolite formation clearances were considered. 5. In conclusion, the disposition of the enantiomers of flurbiprofen exhibits enantioselectivity at the level of protein binding and metabolite formation.     

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.     

Influence of advanced age on the disposition of acetazolamide.

The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly healthy volunteers, each of whom received an intravenous bolus dose of 5 mg/kg. The concentration time profile of AZ was determined in plasma, plasma ultrafiltrate, erythrocytes and urine. While the mean area under unbound plasma concentration-time curves was 81% higher in elderly subjects, areas based on total drug concentrations were similar in both groups. The mean renal plasma clearance was similar in both groups. The mean renal plasma clearance was similar between young and old for total AZ, but was significantly lower in the elderly for unbound drug (8.88 ml min-1 kg-1 vs 15.7 ml min-1 kg-1). Renal clearance of unbound AZ correlated well with creatinine clearance (r = 0.846, P less than 0.01). Peak erythrocyte levels were 45% higher in the elderly group (37.2 micrograms/ml vs 25.3 micrograms/ml) and were paralleled by a 46% increase in the mean area under the erythrocyte concentration-time curve for this age group. The unbound fraction of AZ in plasma was significantly greater in elderly than younger subjects (6.9 vs 4.1%, P less than 0.05). Integrated AZ erythrocyte concentrations correlated positively with AZ free fraction in plasma and inversely with its unbound renal clearance. These observed differences in AZ disposition between elderly and young have served to clarify host factors which may importantly influence susceptibility to adverse effects.     

Naproxen pharmacokinetics in the elderly.

While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/- 0.078, 0.416 +/- 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/- 64, 396 +/- 155 l/h). As a result, mean steady-state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/- 8.5, 58.2 +/- 8.1 mg/l) but the elderly generated twice the mean steady-state unbound plasma drug concentration (0.157 +/- 0.039, 0.0859 +/- 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration-response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly.     

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.     

Single dose pharmacokinetics and pharmacodynamics of oral oxazepam in very elderly institutionalised subjects.

The effect of extreme old age on the pharmacokinetics and pharmacodynamics of orally administered oxazepam 15 mg was studied in 10 healthy elderly (age 80-94 years) institutionalised subjects and 10 healthy young controls (age 26-42 years). The total oxazepam clearance was 1.24 (0.91-1.80) ml min-1 kg-1 (median and range) and 1.44 (0.88-2.13) ml min-1 kg-1 in the elderly and young, respectively (NS), and the elimination half-lives were 8.1 (5.5-10.8) h and 5.7 (4.9-6.2) h. respectively (P less than 0.01). The percent of unbound oxazepam was greater in the elderly; 9.8 (8.1-13.3)% as opposed to 5.1 (3.7-5.9)% in the young (P less than 0.0001). Clearance of unbound oxazepam was lower in the elderly, median values being 13.8 (7.1-21.1) ml min-1 kg-1 compared with 30.3 (18.3-41.5) ml min-1 kg-1 in the young (P less than 0.0001). A single 15 mg dose oxazepam decreased the ability of the elderly to perform a finger tapping test at 3 h but not 8 h after drug administration, whereas placebo had no effect at either times. No effect was observed in the young subjects.     

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.     

Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.     

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.     

The pharmacokinetics of piroxicam in elderly persons with and without renal impairment.

1. Piroxicam pharmacokinetics were assessed in three groups of subjects: (1) young healthy volunteers, (2) healthy elderly subjects (mean +/- s.d. creatinine clearance 88 +/- 13 ml min-1), and (3) elderly patients with renal insufficiency (creatinine clearance 60 +/- 10 ml min-1) following the administration of piroxicam 20 mg as a single dose and after chronic dosing of 20 mg once daily for 4 weeks. 2. Piroxicam and 5'-hydroxypiroxicam concentrations were measured by h.p.l.c. in serum and urine samples collected for 96 h after the single dose and for 144 h after chronic dosing. Unbound concentrations of piroxicam were determined by ultrafiltration. 3. Elimination half-lives, steady state concentrations of piroxicam and 5'-hydroxypiroxicam, clearances of total and unbound piroxicam, volumes of distribution normalized for body weight, and urinary recovery of 5'-hydroxypiroxicam were not influenced by age or renal function. Volumes of distribution after the single dose were significantly lower in women compared with men (mean +/- s.d. 10.0 +/- 2.9 l vs 12.9 +/- 5.0 l; 95% confidence interval of the difference 0.1 to 5.6). 4. Percent unbound piroxicam values were 1.46 +/- 0.3% after the single dose and 1.45 +/- 0.2% at steady state. There were significant reductions in clearance and clearance of unbound piroxicam between single and chronic doses. The half-lives of 5'-hydroxypiroxicam (80.9 +/- 44 h) were significantly longer than those of piroxicam (54.9 +/- 26 h) after chronic dosing.     

The influence of alpha 1-acid glycoprotein on quinine and quinidine disposition in the rat isolated perfused liver preparation.

We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.     

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.     

Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin.

1. The disposition of hexobarbitone enantiomers before and after rifampicin treatment (600 mg daily for 14 days) was investigated in six young (29 +/- 3 years old) and six elderly (71 +/- 4 years old) healthy male volunteers. Hexobarbitone was given as a single 500 mg oral dose of the racemate. 2. The mean (+/- s.d.) oral clearance of S-(+) hexobarbitone was 1.9 +/- 0.3 and 1.8 +/- 0.2 ml min-1 kg-1, respectively, in young and elderly subjects and increased approximately six fold following 14 days of rifampicin treatment in both young (to 11.9 +/- 2.2 ml min-1 kg-1) and elderly (to 10.7 +/- 2.8 ml min-1 kg-1) subjects. 3. In contrast, rifampicin treatment produced a larger and a differential increase in the oral clearance of R-(-) hexobarbitone in young and elderly subjects; an 89 fold change in the young (15.6 +/- 16.4 to 1146.7 +/- 1478.0 ml min-1 kg-1) and a 19 fold change (10.3 +/- 3.0 to 199.9 +/- 98.1 ml min-1 kg-1) in the elderly.     

Stereoselective disposition of flurbiprofen in uraemic patients.

1. Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R- and S-enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2. For R-flurbiprofen the oral clearance (mean +/- s.d.: 38.3 +/- 12.8 vs 30.8 +/- 11.5 ml min-1) and volume of distribution (Vz; 17.6 +/- 3.9 vs 14.6 +/- 2.5 l) were significantly greater (P less than 0.05) than for the S-enantiomer. A significantly greater (P less than 0.05) percent of the dose was excreted in the urine R-configuration (16.4 +/- 6.0 vs 10.9 +/- 4.2%). 3. Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound Vz were not different between enantiomers consistent with the (not significantly) greater percent unbound of R-flurbiprofen (0.079 +/- 0.014%) vs S-flurbiprofen (0.064 +/- 0.015%). 4. Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P less than 0.05) oral clearance, Vz and percent unbound for both enantiomers; unbound clearance and unbound Vz did not differ from healthy controls. 5. The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.     

Free drug metabolic clearance in elderly people

The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a determinant of dosing. Drug clearance has been shown to be consistently impaired for flow-limited (high-clearance) drugs, but there have been conflicting results for capacity-limited (low-clearance) drugs. A limitation of the studies of capacity-limited drugs is that most have estimated clearance based on total drug concentrations (protein-bound plus free). Total drug clearance reflects both the intrinsic clearance of free drug and the extent of protein binding. Total clearance is a valid measure for capacity-limited drugs with low protein binding and appears to be consistently impaired in elderly subjects. For phenazone [antipyrine] (fraction unbound [f(u)] >0.9), seven studies have demonstrated statistical reductions in clearance of 20-52%. For theophylline (f(u) 0.6), five studies have demonstrated reductions in clearance of 22-35%. For paracetamol [acetaminophen] (f(u) 0.8), the clearance of which has been quoted as unchanged, four studies have demonstrated reductions in clearance of 19-35%. For highly protein-bound drugs, total clearance is not the appropriate parameter. Free drug clearance is more appropriate since it is independent of changes in protein binding. The literature was reviewed to test the hypothesis that in elderly people, capacity-limited drugs with high protein binding will show decreased free clearance even in the absence of a decrease in total clearance. For these drugs, data for free drug clearance based on measurement of actual free drug concentrations are limited, but suggest that the intrinsic metabolic clearance is impaired in elderly subjects. Four studies of naproxen (f(u) <0.01) have shown reduced free drug clearance of 50% or more. Two studies of valproic acid (f(u) 0.1-0.2) have shown reduced free clearance of 39% and 65%. Two studies of ibuprofen (f(u) <0.01) have shown reduced free clearance of S-ibuprofen of 21% and 28%. There is some indirect evidence for reduced clearance of the highly protein-bound drugs oxaprozin, temazepam, lorazepam, diazepam, phenytoin and warfarin, although studies measuring free concentrations are lacking. Together, the above studies support the hypothesis that the intrinsic metabolic drug clearance is impaired in elderly subjects, in the order of 20-60%, and that this effect is masked if highly protein-bound drugs are assessed using total drug clearance. If the findings are confirmed in future well-designed studies of free drug clearance, there are profound and beneficial implications for dosing of drugs in elderly people. Lower doses are likely to achieve appropriate concentrations, allowing full efficacy but decreased dose-related adverse effects.     

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.     

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.     

Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R- and S-ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10-5-5 mg/kg) at 24-hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R-ibuprofen into S-ibuprofen was developed using the software NONMEM. R- and S-ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half-life (t((1/2))) of 34.3 hours for S-ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t((1/2)) at birth of 8.3 hours for R-ibuprofen. R-ibuprofen elimination increased during the first week of life, whereas S-ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R- and S-enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R-ibuprofen was elicited.     

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)