Mechanism of the Reduced Elimination Clearance of Benzylpenicillin from Cerebrospinal Fluid in Rats with Intracisternal Administration of Lipopolysaccharide

Abstract

ABSTRACT:The mechanism responsible for the reduced clearance of benzylpenicillin (BPC) from the cerebrospinal fluid (CSF) was investigated in rats that received an intracisternal administration of lipopolysaccharide (LPS). BPC was intraventricularly injected and its elimination from the CSF studied. During the inflammation created by the LPS administration to the cisterna magna, the clearance of BPC and taurine from the CSF was significantly reduced but reverted to the control level when N-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, was intracisternally administered. The in vitro uptake of BPC and taurine was significantly reduced in the choroid plexus (CP, the blood-CSF barrier) of rats with experimental inflammation and in control CP that had been pretreated with sodium nitroprusside (SNP, an NO donor). Interestingly, the clearance and CP uptake of formycin B, a substrate for a nucleoside transporter, were not affected by the experimental inflammation or by pretreatement with SNP. These observations suggest that the BPC transporter, and probably other transport systems as well, is functionally sensitive to NO in the blood-CSF barrier. Therefore, functional impairment of BPC transport in the CP by NO may be partly responsible for the increase in BPC concentration in the CSF during inflammation such as that caused by meningitis.Meningitis, a potentially fatal disease, is characterized by the inflammation of the meninges that cover the brain and the spinal cords. Secondary to the inflammation, alterations in the function of the barriers between the blood/brain (Wispelwey et al., 1988;Roord et al., 1994;Jaworowicz et al., 1998;Xaio et al., 2001) and blood/CSF 1 (Spector and Lorenzo, 1974) have been reported, as evidenced by an increased permeability of normally nonpermeable compounds such as sucrose. In addition to damage to the diffusional barriers, the functional activities of carrier-mediated transports, including penicillins (Lithander, 1965;Spector and Lorenzo, 1974) and glucose (Cooper et al., 1968;Prockop and Fishman, 1968) across the blood-CSF barrier, are reduced with the induction of experimental meningitis. Among these examples, inflammation-dependent change in pharmacokinetics has been studied most extensively for the case of penicillins in the CSF. For example, the intracisternal inoculation of Hemophilus influenzae, has been reported to be associated with a significantly elevated level of ampicillin and BPC in the CSF (Lithander and Lithander, 1966;Spector and Lorenzo, 1974). In addition, a reduction in the transport of BPC was noted in CP (i.e., the blood-CSF barrier) obtained from inflamed rabbits (Spector and Lorenzo, 1974). In general, drug levels in the CSF are partly governed by the kinetics of efflux across the blood-CSF barrier. Therefore, these observations suggest that the transport of BPC from the CSF to the systemic circulation is reduced as the result of the inflammation and that the reduction in the transport is related to the elevation in BPC levels in the CSF of inoculat...

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The BCSFB is involved in the continuous removal of prostaglandin E2 from the CSF, keeping low the intracerebral levels of this proinflammatory mediator [156]. A downregulation of prostaglandin E2 efflux transporters occurs in the models of bacterial meningitis and viral infection, and may exacerbate the effects of neuroinflammation [57,67]. Chronic moderate hyperbilirubinemia Fig.…”

Importance of Peptide Transporter 2 on the Cerebrospinal Fluid Efflux Kinetics of Glycylsarcosine Characterized by Nonlinear Mixed Effects Modeling

“…For example, the active clearance of organic anions in the choroid plexus was strongly impaired by exposure to inflammatory stimuli (33). It has also been reported that the uptake of benzylpenicillin in choroid plexus was reduced and CSF levels was increased in an experimental meningitis model (33-35). These changes can disrupt both the diffusion clearance and active clearance of drugs at BCSFB in our model.…”

Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2 produced in the brain

“…Reduced uptake of benzylpenicillin by the choroid plexus has been reported in rats that received intracisternal LPS, an experimental model of bacterial meningitis (Han et al . ). As rat OAT3 is the transporter responsible for the uptake of benzylpenicillin (Nagata et al .…”

“…Each point represents the mean ± SEM (n = 6-10). been reported in rats that received intracisternal LPS, an experimental model of bacterial meningitis (Han et al 2002). As rat OAT3 is the transporter responsible for the uptake of benzylpenicillin (Nagata et al 2002) and PGE 2 in the choroid plexus, the OAT3-mediated PGE 2 clearance from the CSF would be reduced as a result of inflammation, leading to the continuous accumulation of PGE 2 in the CSF.…”