The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats

Lötsch, Jörn; Schmidt, R.; Vetter, Gregor; Schmidt, Helmut; Skarke, Carsten; Niederberger, Ellen; Geißlinger, Gerd; Tegeder, Irmgard

doi:10.1016/s0304-3940(02)00618-3

Cited by 10 publications

(4 citation statements)

References 21 publications

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“…1). This result agrees with the microdialysis study of Lötsch et al . (2002b), in which the coadministration of probenecid is responsible of a non‐significant 1.3‐fold increase on the dialysate concentration of M6G.…”

Section: Resultssupporting

confidence: 93%

Evidence for an active transport of morphine‐6‐β‐d‐glucuronide but not P‐glycoprotein‐mediated at the blood–brain barrier

Bourasset

Cisternino

Temsamani³

et al. 2003

Journal of Neurochemistry

108

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Morphine-6-b-D-glucuronide (M6G) is an active metabolite of morphine with high analgesic potency despite a low blood-brain barrier (BBB) permeability. The aim of the study was to elucidate its transport mechanism across the BBB. We first checked if M6G was effluxed by the P-glycoprotein (P-gp), as previously reported by others. Second, we investigated the role of anionic transporters like the multidrug resistance-associated protein mrp1 and the glucose transporter GLUT-1. The brain uptake of [ 14 C]M6G was measured by the in situ brain perfusion technique in wild-type and deficient mice [mdr1a(-/-) and mrp1(-/-)], with and without probenecid, digoxin, PSC833 or D-glucose. No difference was found between P-gp and mrp1 competent and deficient mice. The brain uptake of [ 14 C]M6G co-perfused with probenecid in wild-type mice was not significantly different from that found in group perfused with [ 14 C]M6G alone. The co-perfusion of [ 14 C]M6G with digoxin or PSC833 was responsible of a threefold decrease of its uptake in mdr1a competent and deficient mice, suggesting that another transporter than P-gp and sensitive to digoxin and PSC833, may be involved. The co-perfusion of [ 14 C]M6G with D-glucose revealed a threefold decrease in M6G uptake. In conclusion, P-gp and mrp1 are not involved in the transport of M6G at the BBB level in contrast to GLUT-1 and a digoxin-sensitive transporter (probably oatp2), which can actively transport M6G but with a weak capacity.Morphine-6-b-D-glucuronide (M6G) is an active metabolite of morphine (Abbott and Palmour 1988;Paul et al. 1989) which could be a more attractive analgesic than morphine because of its higher potency (Paul et al. 1989;Gong et al. 1991;Osborne et al. 1992) and lower respiratory depressive effects (Thompson et al. 1995;Lö tsch and Geisslinger 2001). Its analgesic activity was extremely potent following intracerebroventricular administration but markedly lower after systemic administration because of its poor blood-brain barrier (BBB) permeability. Several hypotheses have been advanced to explain its low BBB permeability. The first one is related to its weak capacity to cross the BBB by passive diffusion because of its hydrophilicity with an apparent log octanol/water partition coefficient at )2.3 (Murphey and Olsen 1994). M6G was also reported to be 7.5 times less permeable through the rat BBB than morphine (Yoshimura et al. 1973) and similar to that of sucrose, which is considered as not crossing BBB, by an internal carotid artery study in the rat (Bickel et al. 1996). Another explanation results from more recent studies suggesting that the BBB permeability of M6G is restricted by the implication of an efflux mechanism (Bouw et al. 2001; Lötsch et al. 2002a). Several in vitro (Huwyler et al. 1996(Huwyler et al. , 1998 and in vivo studies (Lö tsch et al. 2002a) have suggested that M6G could interact with P-glycoprotein (P-gp), an ABC transporter expressed at the luminal membrane of the brain microvessel endothelial cells forming the BBB. P-gp is known t...

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Section: Resultssupporting

confidence: 93%

Evidence for an active transport of morphine‐6‐β‐d‐glucuronide but not P‐glycoprotein‐mediated at the blood–brain barrier

Bourasset

Cisternino

Temsamani³

et al. 2003

Journal of Neurochemistry

108

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“…This value is close to those found in three other studies testing the effect of probenecid on M6G brain uptake in rats and mice and on M6G miotic effects in humans. In these studies the nonsignificant increase and decrease factors in brain M6G uptakes were 1.3 (Lö tsch et al, 2002) and 1.2 (Bourasset et al, 2003), respectively, and the significant increase factor of the M6G-mediated miotic effect was 1.2 (Skarke et al, 2004). Recently, Tunblad et al (2005) showed that probenecid did not significantly affect the rat brain disposition of M6G but significantly decreased its systemic elimination by a factor of 22%.…”

Section: Discussionmentioning

confidence: 93%

Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-β-d-glucuronide

Bourasset

Scherrmann

2006

Life Sciences

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“…It has been shown that M6G is actively transported across the BBB by transporters such as GLUT1 and digoxin, 40 and probenecid-sensitive transporters. 41 However, there is conflicting evidence as to whether M6G is a substrate of P-gp: it appears to be a P-gp substrate in a rat model and in primary cultured porcine brain capillary endothelial cells but there were no differences in brain uptake and antinociceptive effects of M6G between P-gp knockout and wild-type mice. 40,42 In this study, it was shown that P-gp inhibitors have no effect on M6G uptake into RBE4 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of Bile Salts on the Transport of Morphine-6-Glucuronide in Rat Brain Endothelial Cells

Yang

Zhang

Fawcett

et al. 2011

Journal of Pharmaceutical Sciences

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The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats

Cited by 10 publications

References 21 publications

Evidence for an active transport of morphine‐6‐β‐d‐glucuronide but not P‐glycoprotein‐mediated at the blood–brain barrier

Evidence for an active transport of morphine‐6‐β‐d‐glucuronide but not P‐glycoprotein‐mediated at the blood–brain barrier

Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-β-d-glucuronide

Effect of Bile Salts on the Transport of Morphine-6-Glucuronide in Rat Brain Endothelial Cells

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