The disposition of ketoprofen enantiomers in man

Transcription

1 Br. J. clin. Pharmac. (1988), 26, The disposition of ketoprofen enantiomers in man B. C. SALLUSTIO, Y. J. PURDIE, A. G. WHITEHEAD, M. J. AHERN' & P. J. MEFFIN Departments of Clinical Pharmacology and 'Medicine, The Flinders University of South Australia, Adelaide, South Australia, 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 1-1 for R- ketoprofen and 0.78 (± 0.06) mg 1-1 for S-ketoprofen. 3 Creatinine clearances for the 21 patients ranged from ml min-'. 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. Keywords ketoprofen enantiomers NSAID Introduction Ketoprofen, like all other 2-arylpropionic acids, contains a chiral centre at the carbon alpha to the carboxyl function and therefore exists as R- and S-enantiomers. For ketoprofen, and the 2- arylpropionates in general, anti-inflammatory activity as determined by in vitro cyclo-oxygenase inhibition, resides almost exclusively with the S- enantiomer (Hutt & Caldwell, 1984). 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. We recently demonstrated chiral inversion of ketoprofen in the rabbit (Abas & Meffin, 1987) and, like the inversion reaction, the other clearance processes for R- and S-ketoprofen were also stereoselective, the clearance of the R- enantiomer being nine fold greater than that of the S-enantiomer. To date there is no information on the disposition of the ketoprofen enantiomers in man. Most of the pharmacokinetic studies of ketoprofen have been carried out using analytical methods that do not distinguish between the R-and S- enantiomers. If there is stereoselective metabolism of ketoprofen in man, similar to that described in rabbit, then such studies may have significantly underestimated the concentrations of the pharmacologically active S-enantiomer Correspondence: Ms B. C. Sallustio, Department of Clinical and Experimental Pharmacology, The University of Adelaide, G.P.O. Box 498, Adelaide, South Australia

2 766 B. C. Sallustio et al. and therefore provide no useful information on the time course of the active S-ketoprofen concentrations in man. Methods Twenty-one patients (11 females and 10 males) with classical or definite rheumatoid arthritis (ARA criteria) of mean (± s.e. mean) age of 69 (± 1.1) years and mean (± s.e. mean) weight of 65 (± 2.9) kg who had been taking 200 mg of racemic ketoprofen (Orudis SR) once a day for 12 weeks took part in this study. Just prior to the last dose in week 12 a 0 h blood sample was taken and the 200 mg racemic ketoprofen dose was administered at h. Blood samples were collected at 1, 2, 3, 4, 6 h and then at 2 hourly intervals for 24 h following dosing. Samples were centrifuged, plasma collected and stored at -20 C until analysed. Prior to dosing, patients were asked to empty their bladders and urine was also collected for the entire 24 h period following dosing. Urine was stored at -20 C until analysed. The measurement of plasma and urine R- and S-ketoprofen was carried out using a h.p.l.c. method capable of resolving both enantiomers (Sallustio et al., 1986). Prior to analysis, urine samples underwent mild alkaline hydrolysis as previously described (Abas & Meffin, 1987), in order to measure unconjugated ketoprofen plus ketoprofen glucuronide. Plasma and urine creatinine concentrations were measured by a standard method (Finley et al., 1978). For each subject, the area under the plasma concentration-time curves (AUC) for R- and S- ketoprofen was calculated using the trapezoidal rule (Gibaldi & Perrier, 1975). The time averaged plasma concentration of R- and S-ketoprofen was calculated by dividing the appropriate AUC by the dosing interval in hours. Creatinine clearance was calculated by dividing the urinary excretion rate during the 24 h collection interval by the plasma concentration at the midpoint of the collection interval. Regression analysis of creatinine clearances against time-averaged ketoprofen enantiomer concentrations was carried out for both R- and S-ketoprofen in order to establish whether there were any linear or hyperbolic correlation between the two processes. Results Typical plasma concentration-time profiles for R- and S-ketoprofen in three study patients are shown in Figure 1. For each patient, the plasma 7 E c 0 T 0 c 0 ECo CU ) c 3 r 2 (V'N o Time (h) Figure 1 Representative plasma concentration vs time profile for R-ketoprofen (A), S-ketoprofen (0) and total (R+S) ketoprofen (U) in three patients over the 24 h period following administration of 200 mg racemic ketoprofen. concentrations of the R- and S-enantiomers were similar at all times over the 24 h sampling period but there was considerable variation in the profile between patients. Six patients exhibited a simple absorption profile where maximum concentrations were achieved at approximately 6 h (Figure la), four patients exhibited a lag period of approximately 6 h before any significant absorption took place and maximum plasma concentrations were achieved at approximately 10 h (Figure lb), a further eleven patients exhibited biphasic absorption profiles in which plasma concentrations peaked at approximately 5 h followed by a second rise in concentrations at approximately 14 h (Figure lc). Maximum plasma concentrations varied from 0.62 to 3.45 mg 1-1 for R-ketoprofen and from 0.56 to 3.66 mg 1-l for S-ketoprofen. Individual and mean (± s.e. mean) creatinine clearances, AUC values, time-averaged plasma concentrations and urinary recoveries of R- and S-

3 Disposition of ketoprofen enantiomers 767 Table 1 Steady-state pharmacokinetic parameters calculated following oral administration of 200 mg racemic ketoprofen in 21 elderly patients Urinary excretion A UC C CLcr Totala Enantiomericb Subject (mg h 1-1) (mg 1-1) (ml min-') recovery distribution R S R S R S IR IR IR IR IR IR IR IR IR IR IR IR IR IR IR IR Mean s.e. mean a, percentage of the dose recovered as ketoprofen plus ketoprofen glucuronide. b, recovery of R- and S-enantiomers as a fraction of total recovery. IR, incomplete urine recovery. CLcr, creatinine clearance. C, time averaged plasma concentration. ketoprofen are shown in Table 1. Complete 24 h urine recoveries were only available in 17 patients and from these a mean (± s.e. mean) of 31.4 (±3.1)% of the dose was recovered as unchanged ketoprofen plus ketoprofen glucuronide. This comprised a mean (± s.e. mean) of 43.0 (±0.5)% of the R-enantiomer and 57.0 (±0.5)% of S- enantiomer. Creatinine clearances in the 17 patients with complete urine recoveries varied from 6 to 162 ml min-1. There was no correlation between creatinine clearance and the timeaveraged plasma concentrations of either R- or S-ketoprofen. The r2 values calculated using linear regression were and whilst those calculated for a hyperbolic relationship were and for R- and S-ketoprofen, respectively. Discussion The plasma concentration-time profiles for total (R+S) ketoprofen obtained in this study were similar to those reported by others for sustained release ketoprofen at steady state in elderly patients (Dennis et al., 1985; Christophidis et al., 1986). The individual enantiomer plasma concentration-time profiles do not provide any evidence for significant stereoselective metabolism of ketoprofen enantiomers in man; however, it is possible that the effects of a small degree of inversion are opposed by a slightly higher clearance of the S-enantiomer by other processes. The data suggest that, in terms of total (bound and unbound) drug, half the value of a non-enantiospecific analysis would give a reasonable approximation of the pharmacologically active S-ketoprofen concentration in plasma. These results obtained in man are clearly different from those reported for rabbits in which 9% of R-ketoprofen was inverted to the S- enantiomer in addition to a very large degree of stereoselectivity in clearance processes other than glucuronide conjugation or inversion (Abas & Meffin, 1987). The urine data in this study showed a slightly greater recovery of S-ketoprofen com-

4 768 B. C. Sallustio et al. pared with R-ketoprofen. However, because we were able to recover only approximately 30% of the dose it was again impossible to determine whether the slightly greater recovery of the S- enantiomer in urine was due to a small degree of inversion or to a slightly higher clearance of the S-enantiomer by other processes. Other studies have also reported a higher recovery of S-ketoprofen in urine of subjects administered racemic ketoprofen (Foster et al., 1988a,b) implying some degree of stereoselectivity in the disposition of ketoprofen enantiomers. In man ketoprofen and its metabolites are excreted chiefly in the urine with a negligible amount of ketoprofen eliminated in the faeces (Populaire et al., 1973). Approximately 70% ketoprofen is recovered in urine as the glucuronide conjugate and 0.6% as unconjugated ketoprofen (Upton et al., 1980). There is also a degree of aromatic hydroxylation and esterification to give the methyl ester (Populaire et al., 1973). Consistent with this, in healthy volunteers approximately 70-80% of a dose of ketoprofen was recovered in the urine as unchanged ketoprofen plus glucuronide conjugate in 24 h (Advenier et al., 1983; Foster et al., 1988a,b). In elderly subjects however, the recovery was shown to decrease to between 46% and 61% in 24 h probably reflecting the impaired renal clearance of ketoprofen and its metabolites in the elderly due to diminished renal function (Advenier et al., 1983; Foster et al., 1988b). One possible explanation for the small recovery of the dose as ketoprofen plus glucuronide conjugate in this study may be that although plasma ketoprofen had reached steady state the elimination half-life of the glucuronide conjugate was increased to an extent that this metabolite was not yet at steady state. In view of the 12 week daily dosing regimen this seems highly unlikely and alternative explanations may be provided by enterohepatic recirculation and the ester glucuronide futile cycle. Many hydrophobic aryl acids and their acyl glucuronide conjugates undergo biliary secretion into the intestine at which point the glucuronide conjugate may be eliminated in the faeces or hydrolysed back to the parent acid which can then be reabsorbed leading to enterohepatic recirculation of the parent compound. Enterohepatic recirculation has been demonstrated in rats for ketoprofen (Brune & Lanz, 1985) and the biphasic absorption profiles obtained in this study (Figure lc) may be a reflection of this process in man. In elderly patients diminished renal clearance may give rise to greater quantities of the glucuronide conjugates being secreted into bile and therefore greater quantities of the dose may be eliminated via the faeces. In addition to enterohepatic recirculation it has been demonstrated that compounds metabolised to ester glucuronides are subject to a futile cycle in which net drug clearance depends on conjugation with glucuronic acid, renal clearance of the glucuronide and hydrolysis of the glucuronide back to the parent compound (Meffin et al., 1983). In this way, net drug clearance is sensitive to renal function since a decrease in renal clearance of the glucuronide would result in more of the conjugate being hydrolyzed back to the parent compound. In the case of ketoprofen the other metabolic pathways of aromatic hydroxylation and esterification to give the methyl ester may take on added importance during decreased renal function and the low recovery of the dose may also be due to a greater percentage being excreted as these metabolites which were not detected by our assay. The futile cycle also predicts that ketoprofen net clearance should be sensitive to renal function and several studies have previously reported that the clearance of ketoprofen is significantly decreased in the elderly in whom renal function is impaired (Advenier et al., 1983; Stafanger et al., 1981). In this study however, we have been unable to demonstrate any correlation between ketoprofen time-averaged plasma concentrations and creatinine clearance. Again this may be explained, in part by increased clearance via the faecal route or by aromatic hydroxylation and esterification to the methyl ester. However, alterations in protein binding may be another important complicating factor in the interpretation of these data. The plasma concentrations measured in this study are for total R- and total S-ketoprofen. In man, ketoprofen is highly protein bound in plasma (approximately 99%) (Williams et al., 1981) and although no studies of the protein binding of ketoprofen enantiomers in man are available, the binding to human serum albumin is stereoselective such that the R-enantiomer is more tightly bound than the S-enantiomer (Rendic et al., 1980). Similar enantioselective protein binding has been demonstrated for 2- phenylpropionic acid in the rabbit and uranyl nitrate induced renal dysfunction has been shown to reduce the degree of binding of both enantiomers (Jones etal., 1986). As has been described for 2-phenylpropionic acid, differences in protein binding between enantiomers or changes in protein binding with renal failure may mask differences or changes in the free clearance of the enantiomers (Meffin et al., 1986; Jones et al., 1986). For example the total steady state plasma

5 Disposition of ketoprofen enantiomers 769 concentrations of 2-phenylpropionic acid in rabbits following an infusion of racemic drug were similar for both enantiomers, however, the free plasma concentrations of the S-enantiomer were approximately double those of the R- enantiomer (Meffin et al., 1986). It would have therefore been desirable to measure free enantiomer concentrations in plasma. The total concentrations measured in this study were already at the limits of sensitivity of our assay and, since no radio-labelled ketoprofen was available to us, it was impossible to carry out protein binding measurements. The results of the study indicate that in terms of total concentrations half the value of a nonenantiospecific assay would give a reasonable approximation of the pharmacologically active S-enantiomer concentration in plasma. However, only free drug is biologically active and in view of the possible enantioselective protein binding of the enantiomers of ketoprofen in man it is necessary to carry out further studies in which free enantiomer plasma concentrations can be determined before making any conclusions about the pharmacokinetics of ketoprofen enantiomers. This work was supported by the Arthritis Foundation of Australia (South Australia) and by a Flinders University Research Grant and May and Baker Australia. We thank the administration at the Repatriation General Hospital, Adelaide, for providing beds and nursing staff. We are sad to announce that Dr Peter Meffin died on the 11th November, References Abas, A. & Meffin, P. J. (1987). Disposition of 2- arylpropionic acid nonsteroidal anti-inflammatory Drugs. IV. Ketoprofen disposition. J. Pharmac. exp. Ther., 240, Advenier, C., Roux, A., Gobert, C., Massias, P., Varoquaux, 0. & Flouvat, B. (1983). Pharmacokinetics of ketoprofen in the elderly. Br. 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6 770 B. C. Sallustio et al. Stafanger, G., Larsen, H. W., Hansen, H. & Sorensen, K. (1981). Pharmacokinetics of ketoprofen in patients with chronic renal failure. Scand. J. Rheumatol., 10, Upton, R. A., Buskin, J. N., Williams, R. L., Holford, N. H. G. & Riegelman, S. (1980). Negligible excretion of unchanged ketoprofen, naproxen and probenecid in urine. J. pharm. Sci., 69, Williams, R. L., Upton, R. A., Buskin, J. N. & Jones, R. M. (1981). Ketoprofen-aspirin interactions. Clin. Pharmac. Ther., 30, (Received 21 March 1988, accepted 20 July 1988)