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1.
Pharm Res ; 18(7): 957-63, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11496955

ABSTRACT

PURPOSE: This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Clup) of morphine, quinidine and verapamil. METHODS: Clup of radiolabeled substrates was determined in P-gp-competent and deficient [mdr1a(-/-)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains. RESULTS: Genetic disruption of mdr1a P-gp resulted in 1.3-, 6.6- and 14-fold increases in Clup for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Clup. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC50 values for efflux of 8.6 +/- 2.3 microM and 36 +/- 2 microM, respectively. Verapamil Clup was approximately 50% higher in mdr1a(+/-) vs. mdr1a(+/+) mice; no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Clup to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo. CONCLUSIONS: P-gp decreases Clup of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Clup may be enhanced by P-gp-mediated efflux.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/pharmacokinetics , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/pharmacokinetics , Brain/metabolism , Sex Characteristics , ATP Binding Cassette Transporter, Subfamily B/deficiency , Animals , Antimalarials/blood , Antimalarials/pharmacokinetics , Blood-Brain Barrier/genetics , Calcium Channel Blockers/blood , Calcium Channel Blockers/pharmacokinetics , Dose-Response Relationship, Drug , Female , Male , Mice , Mice, Knockout , Morphine/blood , Morphine/pharmacokinetics , Narcotics/blood , Narcotics/pharmacokinetics , Perfusion/methods , Quinidine/blood , Quinidine/pharmacokinetics , Substrate Specificity/genetics , Verapamil/blood , Verapamil/pharmacokinetics
2.
Pharm Res ; 18(2): 183-90, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11405289

ABSTRACT

PURPOSE: This study was conducted to assess the influence of P-glycoprotein (P-gp) on brain uptake of multidrug resistance sensitive drugs using an in situ brain perfusion technique in P-gp-deficient (mdr1a[-/-]) and wild-type mice. METHODS: The blood-brain transport of radiolabeled vinblastine, vincristine, doxorubicin, colchicine, and morphine was evaluated in mdr1a(-/-) and wild-type CF-1 mice with the in situ brain perfusion technique. Brain uptake of drugs after intravenous pretreatment with P-gp reversal agents, (PSC 833, GF 120918, or (+/-)-verapamil), or vehicle also was studied in wild-type mice. In all experiments, cerebral vascular volume was determined by co-perfusion of sucrose. RESULTS: Cerebral vascular volume was preserved during perfusion, indicating maintenance of blood-brain barrier integrity in both types of mice within the concentration range of substrates in the perfusate. The apparent brain transport of colchicine. vinblastine, doxorubicin, and morphine was increased 3.0, 2.7, 1.5, and 1.4-fold, respectively, in mdr1a(-/-) mice compared with the wild-type: the brain uptake of vincristine was not affected by P-gp. Preadministration of PSC 833 or GF 120918 in wild-type mice led to a -3-fold increase in the brain transport of colchicine and vinblastine, but no effect was observed for the other compounds. Intravenous verapamil enhanced colchicine brain transport (1.8-fold), but failed to increase the brain uptake of vinblastine and morphine. CONCLUSION: The in situ brain perfusion technique appears to be a sensitive and powerful tool for medium throughput screening of the brain uptake of multidrug resistance sensitive drugs. The effect of P-gp is characterized more efficiently with mdr1a(-/-) mice than by using modulators of P-gp in wild-type mice.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Brain/metabolism , Drug Resistance, Multiple/physiology , Tetrahydroisoquinolines , ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Acridines/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Biological Transport , Blood-Brain Barrier , Colchicine/pharmacokinetics , Cyclosporins/pharmacology , Doxorubicin/pharmacokinetics , Isoquinolines/pharmacology , Male , Mice , Perfusion , Time Factors , Verapamil/pharmacology , Vinblastine/pharmacokinetics
3.
Neurosci Lett ; 301(3): 155-8, 2001 Apr 06.
Article in English | MEDLINE | ID: mdl-11257421

ABSTRACT

P-glycoprotein (P-gp) and organic anion transporting polypeptides (Oatp) are expressed at the blood-brain barrier (BBB). There is little functional evidence for Oatp-mediated transport at the BBB. The peptidic delta opioid-receptor agonist [D-penicillamine(2,5)]-enkephalin (DPDPE) is a substrate of mdr1a P-gp and Oatp2. The present study evaluated the influence of these transporters on brain uptake of DPDPE by in situ perfusion in mice. Brain uptake was increased approximately 12-fold in mice lacking P-gp in the BBB, but the P-gp inhibitor dexverapamil did not increase uptake in P-gp-competent mice. In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine. These results confirm P-gp-mediated efflux of DPDPE, and suggest functional uptake transport of DPDPE by Oatp, at the murine BBB.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , ATP-Binding Cassette Transporters/genetics , Analgesics, Opioid/pharmacokinetics , Blood-Brain Barrier/physiology , Enkephalin, D-Penicillamine (2,5)-/pharmacokinetics , Receptors, Opioid, delta/metabolism , Terfenadine/analogs & derivatives , Animals , Anion Transport Proteins , Blood-Brain Barrier/drug effects , Calcium Channel Blockers/pharmacology , Carrier Proteins/metabolism , Digoxin/pharmacology , Enzyme Inhibitors/pharmacology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Histamine H1 Antagonists/pharmacology , Male , Mice , Mice, Knockout , Perfusion , Receptors, Opioid, delta/agonists , Terfenadine/pharmacology , Verapamil/pharmacology
4.
Cancer Metastasis Rev ; 20(1-2): 13-25, 2001.
Article in English | MEDLINE | ID: mdl-11831641

ABSTRACT

Malignant brain tumors and brain metastases present a formidable clinical challenge against which no significant advances have been made over the last decade. Multidrug resistance (MDR) is one of the main factors in the failure of chemotherapy against central nervous system tumors. The MDR1 gene encoding P-glycoprotein (P-gp), a drug efflux pump which plays a significant role in modulating MDR in a wide variety of human cancers, is highly expressed in the blood-brain barrier (BBB). The BBB controls central nervous system exposure to many endogenous and exogenous substances. The exact molecular mechanisms by which the BBB is involved in the resistance of brain tumors to chemotherapy remain to be identified. The purpose of this review is to summarize reports demonstrating that P-gp, one of the most phenotypically important markers of the BBB, is present in primary brain tumors and thus plays a crucial role in their clinical resistance to chemotherapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Blood-Brain Barrier , Brain Neoplasms/drug therapy , Drug Resistance, Multiple , Drug Resistance, Neoplasm , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Brain Neoplasms/metabolism , Humans , Multidrug Resistance-Associated Proteins/metabolism
5.
Eval Rev ; 24(1): 73-91, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10747771

ABSTRACT

This article reports on the theory-driven evaluation of a drop-in center for youth that incorporated a literature search, concept mapping with staff, and focus groups with youth. Findings revealed strong agreement among the three sources of data around specific elements identified as critical components of a program theory of global prevention in after-school-hours initiatives, such as drop-in centers. These results are used to illustrate how a theory-driven approach was relevant for the context and objectives of this evaluation, as well as how it was used to develop knowledge useful for action, social intervention theory, and further research.


Subject(s)
Child Health Services/organization & administration , Community Networks/organization & administration , Social Work/organization & administration , Child , Humans , Program Evaluation
6.
J Cereb Blood Flow Metab ; 20(2): 381-6, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10698076

ABSTRACT

An in situ mouse brain perfusion model predictive of passive and carrier-mediated transport across the blood-brain barrier (BBB) was developed and applied to mdr1a P-glycoprotein (Pgp)-deficient mice [mdr1a(-/-)]. Cerebral flow was estimated from diazepam uptake. Physical integrity of the BBB was assessed with sucrose/inulin spaces; functional integrity was assessed with glucose uptake, which was saturable with a Km of approximately 17 mmol/L and Vmax of 310 mmol x 100 g(-1) x min(-1). Brain uptake of a Pgp substrate (colchicine) was significantly enhanced (two- to fourfold) in mdr1a(-/-) mice. These data suggest that the model is applicable to elucidating the effects of efflux transporters, including Pgp, on brain uptake.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , ATP-Binding Cassette Transporters/genetics , Anesthetics, Intravenous/pharmacokinetics , Blood-Brain Barrier/genetics , Brain/blood supply , Cerebrovascular Circulation/genetics , Diazepam/pharmacokinetics , Animals , Colchicine/pharmacokinetics , Glucose/pharmacokinetics , Inulin/pharmacokinetics , Male , Mice , Mice, Mutant Strains , Perfusion , Sucrose/pharmacokinetics
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