Role of blood‐brain barrier P‐glycoprotein in limiting brain accumulation and sedative side‐effects of asimadoline, a peripherally acting analgaesic drug

Jonker, Johan W.; Wagenaar, Els; Deemter, Liesbeth van; Gottschlich, Rudolf; Bender, H.; Dasenbrock, Johannes; Schinkel, Alfred H.

doi:10.1038/sj.bjp.0702497

Cited by 102 publications

(58 citation statements)

References 26 publications

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“…In contrast to previous studies, we did not detect significant transport of cimetidine by human MDR1 P-gp (Pan et al, 1994;Collett et al, 1999;Karyekar et al, 2003). Also in the well characterized pig-kidney cell line LLC-PK1 transfected with human MDR1, which is routinely used in MDR1 transport experiments (Schinkel et al, 1995;Jonker et al, 1999;Lecureur et al, 2000;Wandel et al, 2000;Karssen et al, 2002), we found no indications for MDR1-mediated cimetidine transport (data not shown). Possibly some MDR1-transfected or -transduced cell lines used in these earlier cimetidine studies display clonal variation in the expression of endogenous BCRP, especially when they are maintained under continuous drug selection (e.g., Pan et al, 1994;Karyekar et al, 2003).…”

Section: Discussioncontrasting

confidence: 54%

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Pávek

Merino²,

Wagenaar³

et al. 2004

J Pharmacol Exp Ther

258

194

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The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter that extrudes xenotoxins from cells, mediating drug resistance and affecting the pharmacological behavior of many compounds. To study the interaction of human wild-type BCRP with steroid drugs, hormones, and the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), we expressed human BCRP in the murine MEF3.8 fibroblast cell line, which lacks Mdr1a/1b P-glycoprotein and Mrp1, and in the polarized epithelial MD-CKII cell line. We show that PhIP was efficiently transported by human BCRP in MDCKII-BCRP cells, as was found previously for murine Bcrp1. Furthermore, we show that six out of nine glucocorticoid drugs, corticosterone, and digoxin increased the accumulation of mitoxantrone in the MEF3.8-BCRP cell line, indicating inhibition of BCRP. In contrast, aldosterone and ursodeoxycholic acid had no significant effect on BCRP. The four most efficiently reversing glucocorticoid drugs (beclomethasone, 6␣-methylprednisolone, dexamethasone, and triamcinolone) and 17␤-estradiol showed a significantly reduced BCRPmediated transepithelial transport of PhIP by MDCKII-BCRP cells, with the highest reduction of PhIP transport ratio for beclomethasone (from 25.0 Ϯ 1.1 to 2.7 Ϯ 0.0). None of the tested endogenous steroids or synthetic glucocorticoids or digoxin, however, were transported substrates of BCRP. We also identified the H 2 -receptor antagonist drug cimetidine as a novel efficiently transported substrate for human BCRP and mouse Bcrp1. The generated BCRP-expressing cell lines thus provide valuable tools to study pharmacological and toxicological interactions mediated by BCRP and to identify new BCRP substrates.The breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP-binding cassette (ABC) family of drug transporters. Human BCRP has been shown to mediate drug resistance through energy-dependent efflux of drug substrates without the need for glutathione. The range of drugs to which BCRP can confer resistance in tumor cell lines includes mi-

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Section: Discussioncontrasting

confidence: 54%

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Pávek

Merino²,

Wagenaar³

et al. 2004

J Pharmacol Exp Ther

258

194

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“…Indeed, and in contrast to tactile allodynia, intraplantar injection of the KOR antagonist nor-BNI did not block the action of asimadoline on formalin-evoked hyperalgesia. However, spinal delivery of nor-BNI was effective, suggesting that even limited penetration of asimadoline in the central nervous system [16,41] could play a role in its capacity to ameliorate formalin-evoked hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

et al. 2006

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Aims/hypothesis We investigated spinal and peripheral kappa opioid systems in diabetic rats. Materials and methods Dynorphin A, N-methyl-D-aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting. Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline. Results Dynorphin A protein levels were significantly increased in peripheral nerves and footpad skin of diabetic rats. Dynorphin A exhibits both anti-and pro-nociceptive properties depending on activation of either KOR or NMDA receptors. Spinal protein levels of these receptors were not changed by diabetes, while KOR levels in the sciatic and peroneal nerves were significantly increased. Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats. Both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats were acutely ameliorated by asimadoline. To confirm that the effect of asimadoline was related to its property as KOR agonist, diabetic rats were pretreated with the selective KOR antagonist nor-binaltorphimine. Intraplantar norbinaltorphimine abolished the ability of asimadoline to alleviate tactile allodynia in diabetic rats. Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats. Conclusions/interpretation Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

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“…Gall bladder cannulation was done as described earlier. 18,19 Briefly, mice were anesthetized with an i.p. injection of a mixture of Hypnorm, Dormicum, and 5% (wt/vol) glucose.…”

Section: Methodsmentioning

confidence: 99%

Mrp2 is essential for estradiol-17β(β-d -glucuronide)-induced cholestasis in rats

et al. 2000

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The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17␤(␤-D-glucuronide) (E 2 17G). Administration of [ 3 H]E 2 17G (18 nmol/g body weight) gave a similar degree of cholestasis and biliary excretion of E 2 17G-equivalents in wild-type and Mdr1a -/-/1b -/-mice. When expressed in Sf9 cells, Bsepmediated adenosine triphosphate (ATP)-dependent transport of taurocholate (TC, 1 mol/L) in membrane vesicles was 110% ؎ 12.5% and 108% ؎ 17.3% of control in the presence of 10 and 50 mol/L E 2 17G, respectively, whereas in rat canalicular membrane, both E 2 17G and the choleretic estradiol-3-␤-D-glucuronide (E 2 3G) inhibited ATP-dependent transport of TC to the same extent. Infusion of The normal liver canalicular membrane expresses a number of adenosine triphosphate (ATP)-binding cassette (ABC) transporters that mediate the active transport of solutes into the canaliculus and are thereby important for the generation of bile and the biliary excretion of a variety of products of endogenous and exogenous origin. 1 MDR1, or the multidrug resistance-1 P-glycoprotein, which is overexpressed in resistant tumor cells, was the first ATP-binding cassette transporter shown to be constitutively expressed in the canalicular membrane. 2 Although its physiological role in the liver is not understood, it transports a wide variety of hydrophobic chemotherapeutic drugs, such as daunorubicin and taxol, 3 in addition to the endogenous metabolite estradiol-17␤(␤-Dglucuronide) (E 2 17G). 4 MDR3/Mdr2 is a phospholipid transporter that translocates phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane from where it is extracted by bile acids and secreted into bile. 5 Mrp2, the liver-specific homologue of the multidrug resistance-associated protein, originally characterized as the canalicular multispecific organic anion transporter, is responsible for the biliary excretion of many glutathione-S-conjugates (e.g., leukotriene C 4 ), glucuronide conjugates (e.g., E 2 17G), and sulfate conjugates. 6,7 Sister-P-glycoprotein, a member of the P-glycoprotein gene family, which is closely related to MDR1 and is highly expressed in liver, 8 has been shown to be the major bile salt export pump (Bsep), which transports bile acids across the canalicular membrane. 9 Bile acids are the most concentrated organic solutes in bile and are considered to be the major driving force for the generation of bile flow. 10 E 2 17G is an endogenous estrogen metabolite that has been shown to decrease bile flow in the rat and bile secretory function in the rhesus monkey. 11 A clear structure-activity relationship for the cholestatic activity of estrogen glucuronides is apparent in that glucuronide conjugates of the estrogen D-ring reversibly induce dose-dependent inhibition of bile flow to yield a family of parallel dose-response curves. In contrast, glucuronide conjug...

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Role of blood‐brain barrier P‐glycoprotein in limiting brain accumulation and sedative side‐effects of asimadoline, a peripherally acting analgaesic drug

Cited by 102 publications

References 26 publications

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

Mrp2 is essential for estradiol-17β(β-d -glucuronide)-induced cholestasis in rats

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