Effects of Clofibric Acid on the Biliary Excretion of Benoxaprofen

ORIGINAL ARTICLES Clinical Pharmaceutics Laboratory, Department of Pharmacy and Health Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats K. Okada, H. Kanoh, K. Mohri Received March 8, 2011, accepted April 15, 2011 Prof. Kiminori Mohri, Clinical Pharmaceutics Laboratory, Department of Pharmacy and Health Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo 204-8588, Japan [email protected] Pharmazie 66: 777–783 (2011) doi: 10.1691/ph.2011.1031 Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+ ) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA. The amounts of (S)-BOP-G in CFA+ rats were 2.7-fold larger than that in CFA- rats. Although (R)-BOP-T was excreted in CFA- rats, BOP-T could not be detected in CFA+ rats. Plasma clearance values of racemic BOP and (S)- BOP in CFA+ rats were 5-fold and 6-fold larger than those in CFA- rats, respectively. (S)-BOP-G formation activities were higher than (R)-BOP-G formation activities in both CFA+ and CFA- microsomes. These findings suggest that CFA increases biliary excretion of (S)-BOP-G and facilitates plasma elimination of BOP, and further suggests that CFA predominantly induces chiral inversion to S rather than metabolic reaction to (R)-BOP-T, resulting in an increase of (S)-BOP-G. 1. Introduction Anti-inflammatory 2-methyl propionic acid derivatives (profens) exhibit stereoselective chiral inversion in vivo from R to S (Caldwell et al. 1988; Iwakawa et al. 1991), and the S enantiomer exhibits an active anti-inflammatory effect (Evans 1992). Chiral inversion of profens progresses with 3 reaction steps. (R)-Acyl-CoA thioester intermediate is formed from the R form by acyl-CoA ligase in the first reaction, chiral inversion of (R)-acyl-CoA to (S)-acyl-CoA intermediate by epimerase occurs in the second reaction, and the S-antipode (free acid) is formed by hydrolysis in the third reaction (Hall and Quan 1994). All 2-methyl propionic acid derivatives, i.e., profens, sold in Japan (ketoprofen, flurbiprofen, ibuprofen (IBP), oxaprofen, tiaprofenic acid, pranoprofen, loxoprofen sodium, alminopro- fen, and zaltoprofen), excluding naproxen (S-form), are used in the racemic form and converted to the S-antipode in vivo (Evans 1992). Fig. 1: Structures of benoxaprofen enantiomers. Benoxaprofen [2 - (4- chlorophenyl)-␣-methyl-5-benzoxazole acetic acid, BOP] (Fig. 1) is a 2-methyl propionic acid deriva- the absolute configuration of the main metabolite, glucuronic tive (profen compound) with anti-inflammatory activity (Cashin acid conjugate (BOP-G), is S, while that of BOP-T is R (Mohri et al. 1977; Tsurumi et al. 1980; Tsurumi et al. 1982). et al. 1998), and that BOP-G is mainly derived from (S)-BOP, We previously reported the presence of its taurine conjugate while BOP-T is derived from (R)-BOP. We also showed that (BOP-T) in rat bile after treatment with, BOP.We also found that chiral inversion from R to S of the parent compound, BOP, is Pharmazie 66 (2011) 777 ORIGINAL ARTICLES closely related to the absolute configurations of these metabolites (Mohri et al. 2005). BOP was recalled from the market and no longer used clinically because of its lethal hepatotoxicity (Duthie et al. 1982; Goudie et al. 1982). However, BOP is the sole model compound of stereoselective amino acid conjugation. It is known that fibrates (fibric acid derivatives) enhance hepatic acyl-CoA synthetase activity involved in fatty acid metabolism and increase the co-substrate, CoA, content (Alegret et al. 1994; Horie et al. 1986). Knights et al. reported that clofibric acid (CFA) treatment promoted formation of an intermediate metabolite of IBP, R-ibuprofenyl-CoA, increasing the R-to-S chiral inversion rate in an experiment using rat liver homogenate (Knights et al. 1991; Shirley et al. 1994). Assuming that fibrates enhance formation of (R)-BOP-CoA intermediate metabolites, promoting metabolism to (R)-BOP-T, we orally administered CFA (280 mg/kg) dissolved in polyethylene glycol to Sprague-Dawley rats for 3 successive days, followed by intravenous administration of BOP (10 mg/kg), and collected blood and bile for 12 h (CFA-pretreated (CFA+ ) group). Polyethylene glycol alone was orally administered for 3 Fig. 2: Plasma concentration-time profiles for racemic BOP (dose: 10 mg/kg body successive days to control rats (CFA-untreated (CFA-) group). weight, n = 6). Polyethylene glycol 400 () 1.0 ml/kg body weight or CFA The pharmacokinetics of BOP enantiomers in plasma were (᭹) 280 mg/kg body weight was administered orally for consecutive 3 days investigated in the CFA+ and CFA- groups, respectively. The before BOP administration. biliary enantiomer levels of BOP and its metabolites (BOP- G and BOP–T) were measured in each group and the biliary significantly lower in the CFA+ group than those in the CFA- excretion rates were determined. It was revealed that CFA pro- group (p < 0.01). In contrast, the elimination rate constant (Kel) moted metabolic reaction: (R)-BOP-CoA → (S)-BOP-CoA → and total body clearance (CLtot) values were 6 and 5 times (S)-BOP → (S)-BOP-G, rather than (R)-BOP-CoA → (R)- greater in the CFA+ group than those in the CFA- group, respec- BOP-T. tively (p < 0.01) (Table 1). These findings indicated that CFA treatment promoted elimination of BOP from plasma. 2. Investigations and results 2.2. Influence of CAF on elimination of BOP 2.1. Influence of CFA on elimination of racemic BOP in enantiomers in rats rats The plasma concentration-time curves of BOP enantiomers The plasma concentration-time curves of racemic BOP in the in the CFA+ and CFA- groups are shown in Fig. 3. In both CFA+ and CFA- groups are shown in Fig. 2. BOP was elimi- groups, (R)-BOP was rapidly eliminated from plasma, while (S)- nated from plasma more rapidly in the CFA+ group than that BOP appeared in plasma after administration of racemic BOP. in the CFA- group. The area under the plasma concentration- The plasma (S)-BOP level started to increase 10 and 20 min time curve (AUC0–12h) and mean residence time (MRT) were after administration in the CFA+ and CFA- groups, respectively. Fig. 3: Plasma concentration-time profiles for BOP enantiomers (dose: racemic BOP 10 mg/kg body weight, each n = 6). (A) polyethylene glycol 400 1.0 ml/kg body weight or (B) CFA 280 mg/kg body weight was administered orally for consecutive 3 days before BOP administration. 778 Pharmazie 66 (2011) ORIGINAL ARTICLES Table 1: Pharmacokinetic parameters of racemate or enantiomers of BOP in clofibric acid treated or untreated rats Parameter Rac.-BOP (R)-BOP (S)-BOP Untreated Treated Untreated Treated Untreated Treated AUC0–12 h(mg h/ml) 0.42 ± 0.01 0.34 ± 0.03* 0.04 ± 0.007 0.03 ± 0.003* 0.40 ± 0.02 0.31 ± 0.03* MRT(h) 53.2 ± 18.6 9.16 ± 1.96* 1.82 ± 0.16 2.42 ± 0.63 65.9 ± 23.1 9.10 ± 2.31* * * * CLtot (ml/h) 1.37 ± 0.55 6.79 ± 0.53 62.3 ± 12.0 109.2 ± 8.41 1.19 ± 0.58 7.55 ± 0.89 Vd(l) 65.6 ± 4.9 61.5 ± 9.1 112.1 ± 14.1 261.9 ± 57.0* 68.7 ± 3.6 67.3 ± 10.2 * * * Kel(1/h) 0.02 ± 0.01 0.12 ± 0.03 0.31 ± 0.02 0.17 ± 0.05 0.02 ± 0.009 0.13 ± 0.03 Treated: clofibric acid treated rats; CFA (+), Untreated: clofibric acid untreated rats; CFA (−). *Significantly different CFA (+) from clofibric acid untreated rats CFA (−)(p < 0.01) (each n = 6). (S)-BOP was eliminated more rapidly in the CFA+ group than those of (S)-BOP-G and (R)-BOP-G were 10.6 ± 1.5 and that in the CFA- group. Tmax and Cmax of (S)-BOP were 2 h 1.8 ± 0.5%, those of (S)-BOP-T and (R)-BOP-T were 0.3 ± 0.04 and 36.1 ␮g/ml in the CFA+ group and 2 h and 35.3 ␮g/ml in and 1.8 ± 0.5%, and those of (S)-BOP and (R)-BOP were the CFA- group, respectively, with no significant differences 0.3 ± 0.2 and 0.03 ± 0.03%, respectively. The cumulative excre- between the groups (p = 0.613). tion rate of (S)-BOP-G was significantly increased (2.7 times) in Table 1 shows the pharmacokinetic parameters (0–12 h) of the CFA+ group compared to that in the CFA- group (p < 0.05), (R)-BOP and (S)-BOP.

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