<i>In vivo</i>evidence for the efflux transport of pentazocine from the brain across the blood–brain barrier using the brain efflux index method

Moriki, Yoshiaki; Suzuki, Toyofumi; Furuishi, Takayuki; Fukami, Toshiro; Tomono, Kazuo; Watanabe, Jun

doi:10.1080/10611860400024110

Cited by 8 publications

(18 citation statements)

References 31 publications

(29 reference statements)

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“…By contrast, there is very little available information about the efflux transport at the BBB concerning the opioid agonist/antagonist analgesics that may be affected by Pgp. Recently, we demonstrated by in vivo approaches that the penetration of pentazocine into the rat brain is restricted by P-gp-mediated efflux (Moriki et al 2004(Moriki et al , 2005, which is consistent with a previous observation in in vitro multidrug resistant cells (Callaghan and Riordan 1993). In order to predict clinically the relevant interactions with P-gp substrates, it is of great importance to clarify the involvement of P-gp in the BBB transport of opioid-related analgesics.…”

Section: Introductionsupporting

confidence: 74%

“…Unlabeled typical P-gp inhibitor, the same as described above, was dissolved in the ECF buffer at pH 7.4 to yield the final concentrations. To examine the dose-dependent effect of unlabeled verapamil, injection solution at the high concentration (4.0 mM) of verapamil was adjusted at pH 7.2 to be dissolved, as described previously (Kusuhara et al 1997;Moriki et al 2005). After microinjection of drug into the cerebrum, aliquots of cerebrospinal fluid (CSF) were collected from the cisterna magma at appropriate times, as reported previously (Kakee et al 1996).…”

Section: Determination Of Bui Into the Brainmentioning

confidence: 99%

“…The in vivo brain efflux study was performed using the intracerebral microinjection technique, as reported previously (Kakee et al 1996;Moriki et al 2005). Rats were anesthetized as described above, and then mounted on a stereotaxic device (SR-6N; Narishige, Tokyo, Japan).…”

Section: Determination Of Bui Into the Brainmentioning

confidence: 99%

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P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

Suzuki

Zaima

Moriki

et al. 2007

Journal of Drug Targeting

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The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood-brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [3H]BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [3H]BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [3H]BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 x 10- 2 min- 1) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [3H]BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part.

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Section: Introductionsupporting

confidence: 74%

Section: Determination Of Bui Into the Brainmentioning

confidence: 99%

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P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

Suzuki

Zaima

Moriki

et al. 2007

Journal of Drug Targeting

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“…By semilogarithmic fitting of the (100 -BEI)-values versus time, the apparent efflux rate constant from the brain (k eff ) is obtained, which is necessary to determine the apparent brain efflux clearance (Cl eff [l 3 t -1 ] (Isakovic et al 2004;Moriki et al 2005;Raybon and Boje 2001;Terasaki 1999):…”

Section: In Situ Brain Perfusionmentioning

confidence: 99%

Brainpeps: the blood–brain barrier peptide database

et al. 2011

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Peptides are able to cross the blood-brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure-property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

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“…As noted previously, there is evidence for a cationic carrier-mediated influx system for pentazocine, DPHM, and other cationic substances (Suzuki et al, 2002a,b). Moriki et al (2005) have provided evidence that P-glycoprotein acts as BBB efflux transporter for this compound. However, DPHM is not a P-glycoprotein substrate (Chen et al, 2003), although we have previously shown that propranolol, which inhibits P-glycoprotein (Bachmakov et al, 2006), significantly increases the brain/plasma ratios of DPHM in adult sheep (Au-Yeung et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Use of Microdialysis for the Study of Drug Kinetics: Central Nervous System Pharmacokinetics of Diphenhydramine in Fetal, Newborn, and Adult Sheep

Au-Yeung

Riggs²,

Gruber³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The central nervous system (CNS) pharmacokinetics of the H 1 receptor antagonist diphenhydramine (DPHM) were studied in 100-and 120-day-old fetuses, 10-and 30-day-old newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at five infusion rates, with each step lasting 7 h. In all ages, cerebrospinal fluid (CSF) and extracellular fluid (ECF) concentrations were very similar to each other, which suggests that DPHM between these two compartments is transferred by passive diffusion. In addition, the brain-to-plasma concentration ratios were >3 in all age groups, suggesting the existence of a transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. However, the ECF/unbound plasma and CSF/unbound plasma DPHM concentration ratios were significantly higher in the fetus and lambs (ϳ5 to 6) than in the adult (ϳ3). The factors f CSF and f ECF , the ratios of DPHM areas under the curves (AUCs) in CSF and ECF to the plasma DPHM AUC, respectively, decreased with age, indicating that DPHM is more efficiently removed from the brain with increasing age. The extent of plasma protein binding of the drug increased with age. This study provides evidence for a transportermediated mechanism for the influx of DPHM into the brain and also for an efflux transporter for the drug, whose activity increases with age. Moreover, the higher brain DPHM levels in the fetus and lamb compared with the adult may explain the greater CNS effects of the drug at these ages.The perinatal period of development is a time of rapid physiological and anatomical changes that can profoundly affect drug disposition. Therefore, caution should be exercised for drug use during pre-and postnatal development due to a poor understanding of age-related changes in drug response and pharmacokinetics (Piper et al., 1987). Of all the issues related to xenobiotic use in the developing fetus and newborn, the effect of drugs on CNS development probably deserves the most attention because exposure to exogenous substances during this dynamic period of neurological growth can potentially cause deleterious effects on the developing brain (Rurak, 1992). Considering the fact that most drugs are lipophilic in nature, these compounds have the ability to cross biological membranes including the bloodbrain barrier (BBB). Diphenhydramine, 2-(diphenylmethoxy)-N,Ndimethylethylamine (DPHM), is a potent histamine H 1 receptor antagonist (Douglas, 1980) widely used for its antiallergic properties, as well as for its antiemetic, sedative, local anesthetic, and hypnotic effects (Runge et al., 1992;Ernst et al., 1993). Like other "firstgeneration" antihistamines, DPHM occupies central H 1 receptors to result in drowsiness, sedation, incoordination and with higher doses, convulsions, and death (Douglas, 1980;Nicholson, 1983;Gengo et al., 1989).In pregnancy, DPHM is used for conditions such as nausea and vomiting, insomnia in the first trimester (Magee et al., 2002), a p...

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In vivoevidence for the efflux transport of pentazocine from the brain across the blood–brain barrier using the brain efflux index method

Cited by 8 publications

References 31 publications

P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood–brain barrier

Brainpeps: the blood–brain barrier peptide database

The Use of Microdialysis for the Study of Drug Kinetics: Central Nervous System Pharmacokinetics of Diphenhydramine in Fetal, Newborn, and Adult Sheep

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