Increased drug delivery to the brain by P-glycoprotein inhibition

Sadeque, Abu

doi:10.1067/mcp.2000.109156

Cited by 391 publications

(248 citation statements)

References 19 publications

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“…Obviously, the results of the present study cannot be extrapolated directly to humans. However, the inhibition of P-gp by quinidine results in respiratory depression by loperamide, which is absent without quinidine, 12 suggesting that the CNS effects of clinically used P-gp substrates is enhanced by P-gp inhibitors.…”

Section: Measurement Of Lidocaine Megx and Bupivacaine In Plasma Andmentioning

confidence: 97%

“…10,11 However, the effects of P-gp inducers or inhibitors on the CNS toxicity of local anesthetics remain unclear. Since local anesthetics are often used in combination with P-gp inhibitors such as verapamil, quinidine and cyclosporine, [12][13][14] examining the effect of P-gp inhibitors on the CNS toxicity of local anesthetics is important. In this study, we examined whether quinidine affects lidocaine-and bupivacaineinduced convulsions.…”

Section: Objectif : Vérifier Si L'inhibition De L'activité Des P-glycmentioning

confidence: 99%

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The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

Funao

Oda

Tanaka

et al. 2003

Can J Anesth/J Can Anesth

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P Pu ur rp po os se e: : To examine whether inhibition of P-glycoprotein (P-gp) activity by quinidine affects the central nervous system toxicity of lidocaine and racemic bupivacaine (bupivacaine).M Me et th ho od ds s: : Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10). Fifteen minutes following administration of 15 mg·kg ) was infused until convulsions occurred. Concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) and bupivacaine in plasma and in the brain at the onset of convulsions were measured by high-performance liquid chromatography.R Re es su ul lt ts s: : There were no differences in the dose of lidocaine required to induce convulsions between the L and QL groups. There were no differences in the concentrations of total (L = 17.2 ± 3.5, QL = 16.6 ± 2.6 µg·mL ) in plasma, total lidocaine or MEGX in the brain at the onset of convulsions between the L and QL groups. The dose of bupivacaine required to induce convulsions was comparable in the B and QB groups. At the onset of convulsions, plasma concentrations of both total (B = 4.9 ± 1.1, QB = 4.0 ± 0.6 µg·mL -1 , P = 0.03) and unbound bupivacaine (B = 1.4 ± 0.6, QB = 0.9 ± 0.2 µg·mL -1 , P = 0.02) were significantly lower in the QB group than in the B group. There were no differences in concentration of total bupivacaine in the brain between the B and QB groups.C Co on nc cl lu us si io on n: : These results suggest that quinidine inhibited P-gp activity, resulting in increased brain/plasma concentration ratio of bupivacaine, but not of lidocaine, and decreased the threshold of plasma concentration for bupivacaine-induced convulsions. (L = 17,2 ± 3,5, QL = 16,6 ± 2, ) et libre (L = 7,8 ± 2,5, QL = 7,3 ± 2, ), entre le MEGX total (L = 1,2 ± 0,5, QL = 1,3 ± 0, ) et libre (L = 0,9 ± 0,5, QL = 0,8± 0,4 (B = 4,9 ± 1,1, QB = 4,0 ± 0, , P = 0,03) et libre (B = 1,4 ± 0,6, QB = 0,9 ± 0 The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats La quinidine, un inhibiteur de P-glycoprotéine, abaisse le seuil des convulsions induites par la bupivacaïne, mais non par la lidocaïne, chez les rats Objectif : Vérifier si l'inhibition de l'activité des P-glycoprotéines (P-gp

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Section: Measurement Of Lidocaine Megx and Bupivacaine In Plasma Andmentioning

confidence: 97%

Section: Objectif : Vérifier Si L'inhibition De L'activité Des P-glycmentioning

confidence: 99%

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

Funao

Oda

Tanaka

et al. 2003

Can J Anesth/J Can Anesth

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“…Instead, we compared the efficacy of tariquidar and DCPQ to enhance brain uptake of [ 11 C]lopramide, which is an avid substrate for P-gp (Sadeque et al, 2000). DCPQ and tariquidar (each at 8 mg/kg i.v.)…”

Section: Effect Of P-gp On Brain Uptake and Peripheral Disposition Ofmentioning

confidence: 99%

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

Yasuno

Brown

Zoghbi

et al. 2007

Neuropsychopharmacol

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The cannabinoid CB 1 receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB 1 receptors in monkey brain. showed that the majority (489%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB 1 receptors in the high binding regions. [ 11 C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4- [(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [ 11 C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier.[ 11 C]MePPEP is a radioligand with high brain uptake, high specific signal to CB 1 receptors, and adequately fast washout from brain that allows quantification with 11 C (half-life ¼ 20 min). These promising results in monkey justify studying this radioligand in human subjects.

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“…A recent study investigated the impact of the C3435T polymorphisms on disposition and brain entry of the Pglycoprotein substrate loperamide, as an indirect measure of P-glycoprotein function in the blood-brain barrier (Table IV). Brain entry was studied by measuring respiratory depression in response to an increased level of CO 2 , as previously established in P-glycoprotein chemical inhibition studies (56). No significant differences in loperamide plasma levels or the extent of respiratory depression could be found between the 3435CC and 3435TT genotypes (57).…”

Section: Impact Of Mdr1 Genetic Variation On Expression and Function mentioning

confidence: 99%

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

2004

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The multidrug resistance (MDR1) gene product P-glycoprotein is a membrane protein that functions as an ATP-dependent efflux pump, transporting exogenous and endogenous substrates from the inside of cells to the outside. Physiological expression of P-glycoprotein in tissues with excretory or protective function is a major determinant of drug disposition and provides a cellular defense mechanism against potentially harmful compounds. Therefore, P-glycoprotein has significant impact on therapeutic efficacy and toxicity as it plays a key role in absorption of oral medications from the intestinal tract, excretion into bile and urine, and distribution into protected tissues such as the brain and testes. There is increasing interest in the possible role of genetic variation in MDR1 in drug therapy. Numerous genetic polymorphisms in MDR1 have been described, some of which have been shown to determine Pglycoprotein expression levels and substrate transport. Furthermore, some of these polymorphisms have an impact on pharmacokinetic and pharmacodynamic profiles of drug substrates and directly influence outcome and prognosis of certain diseases. This review will focus on the impact of genetic variation in MDR1 on expression and function of P-glycoprotein and the implications of this variation for drug therapy and disease risk.

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Increased drug delivery to the brain by P-glycoprotein inhibition

Cited by 391 publications

References 19 publications

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

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