Stereoselective pharmacokinetics of flurbiprofen in humans and rats

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.     

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.     

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 ～ 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.     

Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48-hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite. Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax), oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (less than or equal to 15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2-antagonists and flurbiprofen is unlikely to be clinically important.     

Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers

AIMS: To determine the influence of age on the enantioselective disposition of ibuprofen in humans. METHODS: Healthy young (n = 16; aged 20-36 years) and elderly (n = 16; aged 66-84 years) volunteers were given a 400-mg oral dose of racemic ibuprofen, and blood and urine samples were collected for 24 h post drug administration. Serum concentrations, total and free, and urinary excretion of both enantiomers of ibuprofen together with the urinary excretion of the stereoisomers of the two major metabolites of the drug, both free and conjugated, were determined by high-performance liquid chromatography. RESULTS: Ageing had little effect on the distribution and metabolism of R-ibuprofen, unbound clearance of the R-enantiomer via inversion being approximately two-fold that via noninversion mechanisms in both age groups. In contrast, the free fraction of S-ibuprofen was significantly greater [33%; young 0.48 +/- 0.10%; elderly 0.64 +/- 0.20%] mean difference -0.16; 95% confidence interval (CI) -0.05, -0.27; P < 0.01; and the unbound clearance of the drug enantiomer was significantly lower (28%; young 15.9 +/- 2.2 l min-1; elderly 11.5 +/- 4.1 l min-1; mean difference 4.4; 95% CI 2.12, 6.68; P < 0.001) in the elderly. The metabolite formation clearances of S-ibuprofen via glucuronidation, and oxidation at the 2- and 3- positions of the isobutyl side chain decreased by 24, 28 and 30%, respectively, in the elderly compared with the young, the differences between the two age groups being significant in each case (P < 0.05). CONCLUSIONS: Following administration of racemic ibuprofen age-associated stereoselective alterations in drug disposition have been observed, with the elderly having increased free concentrations and lower unbound clearance of the S-enantiomer in comparison with the young. In contrast, the handling of the R-enantiomer is essentially unaltered with age. The results of this study indicate that the elderly have an increased exposure to the active ibuprofen enantiomer and thus some caution may be required when using this drug in this age group.     

The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy.

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 +/- 3.3 years), 6 nonarthritic elderly subjects (ages 73 +/- 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R-etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S-enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali-labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.     

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.     

The effects of liver and renal disease on stereoselective serum binding of flurbiprofen.

Stereoselectivity in the serum binding of flurbiprofen, a non-steroidal anti-inflammatory drug which is highly bound to albumin, was studied in patients with liver and renal disease. Subjects with renal disease or liver disease with ascites had significantly lower serum albumin concentrations than normals, resulting in higher free fractions of both the R(-) and S(+) enantiomers of flurbiprofen as determined by equilibrium dialysis. The ratio (+/- s.d.) of R/S-flurbiprofen free fractions was lower in the subjects with ascites (0.714 +/- 0.298) than in those without ascites (0.796 +/- 0.090) (P < 0.05).     

Pharmacokinetic interaction between flurbiprofen and antacids in healthy volunteers

Gastrointestinal distress resulting from drug intake is often remedied by administering the drug with antacids. However, antacids have been shown to modify the absorption and excretion of many drugs. This study was designed to delineate the effects of aluminium and magnesium hydroxide antacid suspension (Maalox) on the pharmacokinetics of flurbiprofen. Since this drug is often used in the elderly, not only young healthy but also geriatric healthy male volunteers participated in the study. A group of twelve young and a group of seven geriatric volunteers received, in a crossover design, a single oral dose of 100 mg of flurbiprofen with and without Maalox. A non-stereospecific assay was used to determine the total (R + S enantiomers) of flurbiprofen in plasma. The relative pharmacokinetic parameters of total flurbiprofen determined from plasma samples were Cmax, tmax, Kel, t1/2, and AUC infinity. The results indicate that the co-administration of Maalox with flurbiprofen had no effect on the rate and extent of total flurbiprofen absorption in young volunteers. In geriatric volunteers, the results indicate no effect of the antacid on the extent of drug absorption. There was a trend for lower plasma concentrations of total flurbiprofen with antacid in the geriatric group and hence a reduction in rate of flurbiprofen absorption although differences were not significant. The study also included a steady state determination of the influence of antacid administration on flurbiprofen pharmacokinetics. The group of young volunteers received, from Day 3 to Day 8, 100 mg of flurbiprofen every 12 h with and without Maalox.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes

OBJECTIVE: This study was conducted to examine differences in flurbiprofen metabolism among individuals with the CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. METHODS: Fifteen individuals with the CYP2C9*1/*1 ( n=5), *1/*2 ( n=5), and *1/*3 ( n=5) genotypes received a single 50-mg oral dose of flurbiprofen. Plasma and urine samples were collected over 24 h, and flurbiprofen and 4'-hydroxyflurbiprofen pharmacokinetic data were compared across genotypes. RESULTS: CYP2C9 genotype was a significant predictor of flurbiprofen metabolism and accounted for 59% of the variability in flurbiprofen AUC(0- infinity ), and approximately 50% of the variability in flurbiprofen oral clearance, formation clearance to 4'-hydroxyflurbiprofen, and the 0 to 24-h urinary metabolic ratio of flurbiprofen to 4'-hydroxyflurbiprofen. Flurbiprofen AUC(0- infinity )was significantly higher and all measures of flurbiprofen clearance were significantly lower in the CYP2C9*1/*3 individuals than in those with *1/*1. Significant differences in these parameters were not detected between *1/*2 subjects and *1/*1 subjects. CONCLUSIONS: CYP2C9 genotype is a significant predictor of flurbiprofen disposition in humans by altering CYP2C9-mediated metabolism and reducing systemic clearance. The effects are most pronounced in individuals carrying the *3 allele.     

A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro.

1. The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro. 2. Both enantiomers were metabolised to three major oxidation products: 8-hydroxymianserin, desmethylmianserin and mianserin 2-oxide. Hydroxylation occurred more readily with the S-enantiomer, whereas desmethylmianserin was always the major metabolite of the R-enantiomer. 3. The generation of chemically reactive metabolites exhibited a marginal degree of stereoselectivity, as assessed by irreversible binding of drug to microsomal protein (S greater than or equal to R; P less than or equal to 0.05). 4. The formation of metabolites which were cytotoxic towards human mononuclear leucocytes was greater (P less than or equal to 0.001] for R(-)-mianserin than for S(+)-mianserin and showed a significant correlation with N-demethylation (r = 0.84, P less than or equal to 0.01).     

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.     

Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4'-nitrowarfarin (acenocoumarol)

1. Rat liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) has been studied. The enantiomers of both compounds were hydroxylated mainly at the 6- and 7-positions. Acenocoumarol enantiomers were much better substrates for cytochromes P-450 than the corresponding warfarin enantiomers; Km values for the 6- and 7-hydroxylations were 2 to 19 times lower for R- and S-acenocoumarol than for warfarin. 2. Formation of the 6-, 7-, and 8-hydroxy-metabolites of warfarin was stereoselective for the R-enantiomer (the R/S ratio for total intrinsic clearance was about 3). 4'-Hydroxylation was not stereoselective. In contrast, formation of acenocoumarol metabolites was stereoselective for the S-enantiomer (the S/R ratio for total intrinsic clearance was about 3). 3. From the effects of phenobarbitone and methylcholanthrene induction, and inhibition by cimetidine, on in vitro metabolism of the enantiomers of both compounds, it was concluded that the differences between warfarin and acenocoumarol can be explained partly by the involvement of different enzymes.     

Analysis of flurbiprofen, ketoprofen and etodolac enantiomers by pre-column derivatization RP-HPLC and application to drug-protein binding in human plasma

A stereoselective reversed-phase high-performance liquid chromatography (HPLC) assay to determine the enantiomers of flurbiprofen, ketoprofen and etodolac in human plasma was developed. Chiral drug enantiomers were extracted from human plasma with liquid–liquid extraction. Then flurbiprofen and ketoprofen enantiomers reacted with the acylation reagent thionyl chloride and pre-column chiral derivatization reagent (S)-(−)--(1-naphthyl)ethylamine (S-NEA), and etodolac enantiomers reacted with S-NEA using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as coupling agents. The derivatized products were separated on an Agilent Zorbax C₁₈ (4.6 mm × 250 mm, 5 μm) column with a mixture of acetonitrile–0.01 mol·L⁻¹ phosphate buffer (pH 4.5) (70:30, v/v) for flurbiprofen enantiomers, acetonitrile–0.01 mol·L⁻¹ phosphate buffer (pH 4.5) (60:40, v/v) for ketoprofen enantiomers and methonal–0.01 mol·L⁻¹ potassium dihydrogen phosphate buffer (pH 4.5) (88:12, v/v) for etodolac enantiomers as mobile phase. The flow of mobile phase was set at 0.8 mL·min⁻¹ and the detection wavelength of UV detector was set at 250 nm for flurbiprofen and ketoprofen enantiomers and 278 nm for etodolac enantiomers. The assay was linear from 0.5 to 50 μg·mL⁻¹ for each enantiomer. The inter- and intra-day precision (R.S.D.) was less than 10% and the average extraction recovery was more than 87% for each enantiomer. The limit of quantification for the method was 0.5 μg·mL⁻¹ (R.S.D. < 10%, n = 5). The method developed was used to study the drug–protein binding of flurbiprofen, ketoprofen and etodolac enantiomers in human plasma. The results showed that the stereoselective binding of etodolac enantiomer was observed and flurbiprofen and ketoprofen enantiomers were not.     

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.2 +/- 17.0 vs 44.6 +/- 11.2 micrograms ml-1h) elimination half-life (5.6 +/- 1.4 vs 4.0 +/- 1.0 h) and mean residence time (7.5 +/- 1.6 vs 5.7 +/- 1.2 h) were observed after 50 mg (S)-flurbiprofen as compared with 50 mg (R)-flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)-flurbiprofen did not differ significantly. The data are of clinical relevance if (R)-flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.     

Selective Effect of Adjuvant Arthritis on the Disposition of Propranolol Enantiomers in Rats Detected Using a Stereospecific HPLC Assay

Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.     

Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4′-nitrowarfarin (Acenocoumarol)

1. Rat liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol (4′-nitrowarfarin) has been studied. The enantiomers of both compounds were hydroxylated mainly at the 6- and 7-positions. Acenocoumarol enantiomers were much better substrates for cytochromes P-450 than the corresponding warfarin enantiomers; K_m values for the 6- and 7-hydroxylations were 2 to 19 times lower for R- and S-acenocoumarol than for warfarin.

2. Formation of the 6-, 7-, and 8-hydroxy-metabolites of warfarin was stereoselective for the R-enantiomer (the R/S ratio for total intrinsic clearance was about 3). 4′-Hydroxylation was not stereoselective. In contrast, formation of acenocoumarol metabolites was stereoselective for the S-enantiomer (the S/R ratio for total intrinsic clearance was about 3).

3. From the effects of phenobarbitone and methylcholanthrene induction, and inhibition by cimetidine, on in vitro metabolism of the enantiomers of both compounds, it was concluded that the differences between warfarin and acenocoumarol can be explained partly by the involvement of different enzymes.     

Minimal in vivo activation of CYP2C9-mediated flurbiprofen metabolism by dapsone.

Dapsone has been shown to activate flurbiprofen 4'-hydroxylation by expressed CYP2C9 enzyme and in human liver microsomes. It has been suggested that this observation is due to substrate cooperativity on enzyme activity; however, the in vivo relevance of this observation is unknown. Thus, the purpose of this study was to evaluate whether dapsone can act cooperatively with flurbiprofen to activate the in vivo metabolism of flurbiprofen to 4'-hydroxyflurbiprofen. Twelve healthy subjects received single-dose flurbiprofen 50 mg on three occasions: alone (visit A); 2 h after a single dapsone 100-mg dose (visit B); and 2 h after the seventh daily dose of dapsone 100 mg (visit C). Concentrations of flurbiprofen and 4'-hydroxy flurbiprofen in plasma and urine and dapsone and N-acetyldapsone in plasma were determined by HPLC. Flurbiprofen pharmacokinetic parameters for the three visits were estimated by non-compartmental methods and compared in the absence and presence of dapsone. Flurbiprofen apparent oral clearance was increased by approximately 11% (P < 0.02) after dapsone 100 mg for 7 days. Dapsone plasma concentrations averaged 5 +/- 2 microM after a single dose and 11 +/- 4 microM after seven daily 100 mg doses. These dapsone plasma concentrations were within the range of concentrations producing activation of flurbiprofen metabolism by CYP2C9 in vitro. These results are consistent with the hypothesis that dapsone does influence flurbiprofen metabolism in vivo in a cooperative way to enhance metabolism. However, the magnitude of effect is substantially less than observed in vitro.     

Effect of experimental diabetes mellitus on the pharmacokinetics of atenolol enantiomers in rats

The effect of streptozotocin-induced diabetes mellitus on the pharmacokinetics of the enantiomers of atenolol (AT) was investigated in rats 3 and 9 days after induction of the disease. Occurrence of diabetes was confirmed by a significant increase (p less than 0.05) in the serum glucose concentration (mg%) of the diabetic rats compared with their respective controls in both 3- (441 +/- 66.3 versus 181 +/- 31.3) and 9- (602 +/- 133 versus 187 +/- 20.0) day diabetic groups. Creatinine clearance (CLcr; mL/min/kg) in 9-day diabetic rats (8.98 +/- 3.02) was significantly higher than that in the controls (4.59 +/- 1.08). However, compared with the control animals, the increase in CLcr of the 3-day diabetic rats (8.35 +/- 1.95 versus 6.82 +/- 1.63) was not significant (p greater than 0.05). The changes in CLcr paralleled those in renal clearance (CLr) values of the AT enantiomers; 9-day diabetes induced a significant increase in CLr of the AT enantiomers (82.4 and 81.6% increase for S(-)-and R(+)-enantiomers, respectively). An increase in CLr values of the AT enantiomers in 3-day diabetic rats, on the other hand, did not reach statistical significance. Furthermore, a significant increase (55.4 and 52.6% for S(-)- and R(+)-AT, respectively) in the nonrenal clearance values of the AT enantiomers was observed in the 3-day, but not 9-day diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)