Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats

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Abstract

The effect of endotoxin on glucuronidation and hepatobiliary transport of quinolone antimicrobial agents was investigated in rats using sparfloxacin and p-nitrophenyl glucuronide as model drugs. The biliary clearance experiments were performed 24 h after a single intraperitoneal injection of endotoxin (1 mg/kg). Endotoxin significantly delayed the disappearance of sparfloxacin from plasma and increased plasma concentration of its glucuronide after intravenous injection of sparfloxacin (10 mg/kg). Significant decreases in the systemic clearance of sparfloxacin and the biliary clearance of sparfloxacin and the glucuronide were observed. Endotoxin had no effect on in vitro glucuronidation activity using p-nitrophenol as a substrate. When p-nitrophenyl glucuronide (8 mg/kg) was administered in endotoxin-pretreated rats, significant decreases in the systemic clearance, biliary clearance and renal clearance of p-nitrophenyl glucuronide were observed. These findings suggest that endotoxin decreases the biliary excretion of sparfloxacin and its glucuronide probably due to impairment of their hepatobiliary transport systems and renal handling.

Introduction

Endotoxin, an active component in the outer membrane of the Gram-negative bacteria, is well known to induce damage to numerous organs including the liver Hirata et al., 1980, Durham et al., 1990, Hewett and Roth, 1993. Among numerous organs, liver has an important function for the detoxication (phase I and phase II metabolism) and excretion (hepatobiliary excretion) of a variety of drugs and their metabolites. The effect of endotoxin and inflammatory cytokines released by endotoxin on phase I metabolism is well known. Studies in our laboratories with antipyrine as a substrate showed that endotoxin treatment induces time-dependent reduction in hepatic metabolism in rats and the reduction is due to overproduction of nitric oxide (NO) in plasma Nadai et al., 1998, Kitaichi et al., 1999. Furthermore, we previously reported that endotoxin treatment impairs biliary and renal excretion of various organic anion drugs by changing the ability of the biliary and tubular secretory systems Nadai et al., 1993a, Nadai et al., 1993b, Nadai et al., 1996, Hasegawa et al., 1994, Haghgoo et al., 1994. However, less is known about the effect of endotoxin treatment on phase II metabolism and hepatobiliary transport systems.

It is well known that several drug transporters contribute to the hepatobiliary transport of drugs; for example, canalicular multispecific organic anion transporter (mrp2/cMOAT) and P-glycoprotein, which belong to ATP-binding cassette (ABC) transporter superfamily, present in the bile canalicular membrane and are considered to play a central role in the excretion of numerous xenobiotics from the liver. There are a number of papers suggesting that organic anions, including glucuronide conjugates, can be secreted into the bile by mrp2/cMOAT Hirohashi et al., 1999, Kamisako et al., 1999, Fukumura et al., 1998, Seitz et al., 1998, Keppler et al., 1997.

New quinolone antimicrobial agents are widely used for the treatment of patients with Gram-negative bacterial infection. Many new quinolone antimicrobial agents (enoxacin, levofloxacin, ciprofloxacin, sparfloxacin and grepafloxacin) are known to primarily excrete into the urine. Among them, sparfloxacin and grepafloxacin are typical groups of drugs excreted into the bile Matsunaga et al., 1991, Akiyama et al., 1995. It has been suggested that grepafloxacin and its glucuronide are exported into the bile by mrp2/cMOAT and that grepafloxacin glucuronide has higher affinity with the transporter than the parent drug (Sasabe et al., 1998). The hepatobiliary transport mechanism of sparfloxacin remains to be elucidated. We consider that sparfloxacin may be also actively excreted into the bile by the same transporter as grepafloxacin or by P-glycoprotein since sparfloxacin is suggested to be a substrate for P-glycoprotein Cormet-Boyaka et al., 1998, Dautrey et al., 1999. However, the effect of endotoxin on the phase II metabolism and hepatobiliary transport of sparfloxacin has not yet been fully clarified.

The aim of the present study is to clarify the effect of Klebsiella pneumoniae endotoxin on the hepatobiliary excretion of quinolones using sparfloxacin and p-nitrophenyl glucuronide as model drugs.

Section snippets

Materials

Endotoxin was isolated from K. pneumoniae LEN-1 (O3: K1), which was identical to that used in previous studies Nadai et al., 1998, Kitaichi et al., 1999. Sparfloxacin was kindly donated from Dainippon Pharmaceutical (Tokyo, Japan). β-Glucuronidase, UDP–glucuronic acid, p-nitrophenol and p-nitrophenyl glucuronide were purchased from Sigma (St. Louis, MO). All other reagents are commercially available and were of analytical grade.

Animals and experiments

Eight- to nine-week-old male Wistar rats weighing 280–300 g (Japan

Effect of endotoxin on the pharmacokinetics of sparfloxacin and the glucuronide

We investigated the effect of endotoxin on the plasma concentration and biliary excretion of sparfloxacin and the glucuronide in rats. Fig. 1 shows mean plasma concentration–time curves of sparfloxacin and the glucuronide in the control and endotoxin-treated rats following an intravenous injection of sparfloxacin (10 mg/kg). As illustrated in Fig. 1, endotoxin dramatically delayed the disappearance of sparfloxacin from plasma and significantly increased the plasma concentrations of sparfloxacin

Discussion

Our interest in the biliary transport of quinolones was stimulated by a report that the transport of grepafloxacin and the main metabolite, grepafloxacin glucuronide, across the bile canalicular membrane is mediated by mrp2/cMOAT and that the glucuronide has a much higher affinity for mrp2/cMOAT than the parent drug (Sasabe et al., 1998). Recently, Tamai et al. (2000) reported on the possible involvement of P-glycoprotein in the blood/brain distribution of grepafloxacin and sparfloxacin.

Acknowledgements

The authors are extremely grateful to Dainippon Pharmaceutical for the generous contribution of drug. This work was supported in part by Grant-in-Aid for Scientific Research (13672417) from the Ministry of Education, Science, Sport, and Culture of Japan and by a grant from the Imanaga Medical Foundation.

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