Enantioselective disposition of a model non-steroidal anti-inflammatory drug 2-phenylpropionic acid

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 (V.; 17.6 ± 3.9 vs 14.6 ± 2.5 1) were significantly greater (P < 0.05) than for the S-enantiomer. A significantly greater (P < 0.05) percent of the dose was excreted in the urine in the 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 V, were not different between enantiomers consistent with the (not significantly) greater percent unbound of Rflurbiprofen (0.079 ± 0.014%) vs S-flurbiprofen (0.064 ± 0.015%). 4 Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P < 0.05) oral clearance, V, and percent unbound for both enantiomers; unbound clearance and unbound V, 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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stereoselective disposition of flurbiprofen in uraemic patients.

Knadler

Brater

Hall

1992

“…With the exception of naproxen, all of the 2-arylpropionic acids in clinical use are marketed as the racemic forms. It has been shown that, in vivo, these compounds undergo stereospecific metabolic chiral inversion from the inactive R form to the pharmacologically active S form (Caldwell et al, 1988;Meffin et al, 1986;Hayball & Meffin, 1987; Abas & Meffin, 1987) so that the R-enantiomer acts as a prodrug for the S-enantiomer.…”

Section: Introductionmentioning

confidence: 99%

The disposition of ketoprofen enantiomers in man.

Sallustio

Purdie

Whitehead

et al. 1988

1. The disposition of ketoprofen enantiomers was studied in 21 patients taking racemic ketoprofen (Orudis SR). 2. In each patient the plasma concentrations of the R‐ and S‐enantiomers were similar at all times over a 24 h dosing interval. The mean (+/‐ s.e. mean) time‐averaged plasma ketoprofen concentrations over the dosage interval were 0.76 (+/‐ 0.06) mg l‐1 for R‐ketoprofen and 0.78 (+/‐ 0.06) mg l‐1 for S‐ ketoprofen. 3. Creatinine clearances for the 21 patients ranged from 6‐ 162 ml min‐1. There was no correlation between creatinine clearance and time‐averaged plasma concentration for either R‐ or S‐ketoprofen. 4. Approximately 30% of the dose was recovered in urine (unconjugated + glucuronide conjugate) and this was made up of 43% R‐ketoprofen and 57% S‐ketoprofen. Because of incomplete urine recoveries of ketoprofen it was not possible to determine whether inversion from the R‐ to the S‐ enantiomer takes place in man. 5. The data suggest that in terms of total (bound + unbound) ketoprofen, half the concentration value derived by a non‐enantiospecific analysis would give a reasonable approximation of the pharmacologically active S‐enantiomer concentration in plasma.

“…Obviously, the (R):(S) AUC ratio is not a measure of the absolute extent of chiral inversion. However, based on the 'futile cycle' model proposed for a chiral structural homologue of ketoprofen, 2-phenylpropanoic acid [23], a renallyinduced net decrease in clearance of the (R)-enantiomer would disproportionately increase the plasma concentrations of its optical antipode due to increased fractional inversion. The extent of this will depend on the degree of chiral inversion of the 2-arylpropanoate.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have examined the influence of renal function on the disposition of 2-arylpropanoic acid NSAIDs, and still fewer have addressed this issue with regard to unbound drug concentrations [11,23,24]. No studies have described the disposition of ketoprofen enantiomers in terms of unbound drug.…”

Section: Introductionmentioning

confidence: 99%

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

Hayball

Nation

Bochner

et al. 1993

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 ,ug 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 ,ug ml-l than that at enantiomer concentrations of 3.50 ,ug ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 ,ug ml-l. 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.