;PMID: 9020195 ;source_file_1730.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..37] = [t:0..37] ;1)sentence:[e:43..121] = [t:43..121] ;2)section:[e:125..178] = [t:125..178] ;3)section:[e:182..280] = [t:182..280] ;4)sentence:[e:284..383] = [t:284..383] ;5)sentence:[e:384..496] = [t:384..496] ;6)sentence:[e:497..650] = [t:497..650] ;7)sentence:[e:651..757] = [t:651..757] ;8)sentence:[e:758..924] = [t:758..924] ;9)sentence:[e:925..1058] = [t:925..1058] ;10)sentence:[e:1060..1174] = [t:1060..1174] ;11)sentence:[e:1175..1388] = [t:1175..1388] ;12)section:[e:1392..1436] = [t:1392..1436] ;section 0 Span:0..37 ;Toxicology. 1997 Feb 14;117(1):13-23. (SEC (FRAG (NNP:[0..10] Toxicology) (,:[10..11] .) (CD:[12..16] 1997) (NNP:[17..20] Feb) (CC:[21..28] 14;117-LRB-) (CD:[28..29] 1) (-RRB-:[29..30] -RRB-) (::[30..31] :) (CD:[31..36] 13-23) (.:[36..37] .))) ;sentence 1 Span:43..121 ;Interaction of methadone with substrates of human hepatic cytochrome P450 ;3A4. ;[58..67]:substance:"methadone" ;[73..83]:substance:"substrates" ;[101..120]:cyp450:"cytochrome P450 3A4" (SENT (NP-SBJ (NP (NN:[43..54] Interaction)) (PP (IN:[55..57] of) (NP (NN:[58..67] methadone))) (PP (IN:[68..72] with) (NP (NP (NNS:[73..83] substrates)) (PP (IN:[84..86] of) (NP (JJ:[87..92] human) (JJ:[93..100] hepatic) (NML (NN:[101..111] cytochrome) (NN:[112..116] P450)) (NN:[117..120] 3A4))))) (.:[120..121] .))) ;section 2 Span:125..178 ;Iribarne C, Dreano Y, Bardou LG, Menez JF, Berthou F. (SEC (FRAG (NNP:[125..133] Iribarne) (NNP:[134..135] C) (,:[135..136] ,) (NNP:[137..143] Dreano) (NNP:[144..145] Y) (,:[145..146] ,) (NNP:[147..153] Bardou) (NNP:[154..156] LG) (,:[156..157] ,) (NNP:[158..163] Menez) (NNP:[164..166] JF) (,:[166..167] ,) (NNP:[168..175] Berthou) (NNP:[176..178] F.))) ;section 3 Span:182..280 ;Equipe d'Accueil EA 948, Laboratoires de Biochimie-Nutrition, Faculte de ;medecine, Brest, France. (SEC (FRAG (NN:[182..188] Equipe) (NN:[189..198] d'Accueil) (NNS:[199..201] EA) (CD:[202..205] 948) (,:[205..206] ,) (NNP:[207..219] Laboratoires) (IN:[220..222] de) (NNP:[223..233] Biochimie-) (NNP:[233..242] Nutrition) (,:[242..243] ,) (NNP:[244..251] Faculte) (IN:[252..254] de) (NN:[256..264] medecine) (,:[264..265] ,) (NNP:[266..271] Brest) (,:[271..272] ,) (NNP:[273..279] France) (.:[279..280] .))) ;sentence 4 Span:284..383 ;Methadone, a synthetic drug, is one of the most widely used drugs for opiate ;dependency treatment. ;[284..293]:substance:"Methadone" ;[307..311]:substance:"drug" ;[344..349]:substance:"drugs" ;[354..360]:substance:"opiate" (SENT (S (NP-SBJ (NP (NN:[284..293] Methadone)) (,:[293..294] ,) (NP (DT:[295..296] a) (JJ:[297..306] synthetic) (NN:[307..311] drug))) (,:[311..312] ,) (VP (VBZ:[313..315] is) (NP-PRD (NP (CD:[316..319] one)) (PP (IN:[320..322] of) (NP (NP (DT:[323..326] the) (ADJP (ADVP (RBS:[327..331] most) (RB:[332..338] widely)) (VBN:[339..343] used)) (NNS:[344..349] drugs)) (PP (IN:[350..353] for) (NP (NML (NN:[354..360] opiate) (NN:[362..372] dependency)) (NN:[373..382] treatment))))))) (.:[382..383] .))) ;sentence 5 Span:384..496 ;This drug has been demonstrated to be extensively metabolized by cytochrome ;P450 3A4 in human liver microsomes. ;[389..393]:substance:"drug" ;[450..469]:cyp450:"cytochrome P450 3A4" (SENT (S (NP-SBJ-1 (DT:[384..388] This) (NN:[389..393] drug)) (VP (VBZ:[394..397] has) (VP (VBN:[398..402] been) (VP (VBN:[403..415] demonstrated) (S (NP-SBJ-1 (-NONE-:[415..415] *)) (VP (TO:[416..418] to) (VP (VB:[419..421] be) (ADVP (RB:[422..433] extensively)) (VP (VBN:[435..446] metabolized) (NP-1 (-NONE-:[446..446] *)) (PP (IN:[447..449] by) (NP-LGS (NN:[450..460] cytochrome) (NN:[461..465] P450) (NN:[466..469] 3A4))) (PP-LOC (IN:[470..472] in) (NP (JJ:[473..478] human) (NN:[479..484] liver) (NNS:[485..495] microsomes)))))))))) (.:[495..496] .))) ;sentence 6 Span:497..650 ;Thus, the aim of this in vitro study was to determine if methadone is an ;inhibitor of other P450s characterized by their specific catalytic ;activities. ;[555..564]:substance:"methadone" ;[571..580]:substance:"inhibitor" ;[590..595]:cyp450:"P450s" (SENT (S (ADVP (RB:[497..501] Thus)) (,:[501..502] ,) (NP-SBJ-1 (NP (DT:[503..506] the) (NN:[507..510] aim)) (PP (IN:[511..513] of) (NP (DT:[515..519] this) (ADJP (FW:[520..522] in) (FW:[523..528] vitro)) (NN:[529..534] study)))) (VP (VBD:[535..538] was) (S-PRP-PRD (NP-SBJ-1 (-NONE-:[538..538] *)) (VP (TO:[539..541] to) (VP (VB:[542..551] determine) (SBAR (IN:[552..554] if) (S (NP-SBJ (NN:[555..564] methadone)) (VP (VBZ:[565..567] is) (NP-PRD (NP (DT:[568..570] an) (NN:[571..580] inhibitor)) (PP (IN:[581..583] of) (NP (NP (JJ:[584..589] other) (NNS:[590..595] P450s)) (VP (VBN:[597..610] characterized) (NP (-NONE-:[610..610] *)) (PP (IN:[611..613] by) (NP-LGS (PRP$:[614..619] their) (JJ:[620..628] specific) (JJ:[629..638] catalytic) (NNS:[639..649] activities)))))))))))))) (.:[649..650] .))) ;sentence 7 Span:651..757 ;Enzymatic activities specific to P450 2E1, P450 1A, P450 2B and P450 2C were ;not inhibited by methadone. ;[685..693]:cyp450:"P450 2E1" ;[695..702]:cyp450:"P450 1A" ;[704..711]:cyp450:"P450 2B" ;[716..723]:cyp450:"P450 2C" ;[747..756]:substance:"methadone" (SENT (S (NP-SBJ-1 (NP (JJ:[651..660] Enzymatic) (NNS:[661..671] activities)) (ADJP (JJ:[673..681] specific) (PP (TO:[682..684] to) (NP (NP (NN:[685..689] P450) (NN:[690..693] 2E1)) (,:[693..694] ,) (NP (NN:[695..699] P450) (NN:[700..702] 1A)) (,:[702..703] ,) (NP (NN:[704..708] P450) (NN:[709..711] 2B)) (CC:[712..715] and) (NP (NN:[716..720] P450) (NN:[721..723] 2C)))))) (VP (VBD:[724..728] were) (RB:[729..732] not) (VP (VBN:[733..742] inhibited) (NP-1 (-NONE-:[742..742] *)) (PP (IN:[743..745] by) (NP-LGS (NN:[747..756] methadone))))) (.:[756..757] .))) ;sentence 8 Span:758..924 ;Conversely, nifedipine oxidation, mediated by cytochrome P450 3A4, was ;potently inhibited by methadone by a mixed-type inhibition mechanism with a ;Ki of 100 microM. ;[770..780]:substance:"nifedipine" ;[804..823]:cyp450:"cytochrome P450 3A4" ;[852..861]:substance:"methadone" ;[907..909]:quantitative-name:"Ki" ;[913..916]:quantitative-value:"100" ;[917..923]:quantitative-units:"microM" (SENT (S (ADVP (RB:[758..768] Conversely)) (,:[768..769] ,) (NP-SBJ-1 (NP (NN:[770..780] nifedipine) (NN:[781..790] oxidation)) (,:[790..791] ,) (VP (VBN:[792..800] mediated) (NP (-NONE-:[800..800] *)) (PP (IN:[801..803] by) (NP-LGS (NN:[804..814] cytochrome) (NN:[815..819] P450) (NN:[820..823] 3A4))))) (,:[823..824] ,) (VP (VBD:[826..829] was) (ADVP (RB:[830..838] potently)) (VP (VBN:[839..848] inhibited) (NP-1 (-NONE-:[848..848] *)) (PP (IN:[849..851] by) (NP-LGS (NN:[852..861] methadone))) (PP-MNR (IN:[862..864] by) (NP (DT:[865..866] a) (NML (VBN:[867..872] mixed) (HYPH:[872..873] -) (NN:[873..877] type)) (NN:[878..888] inhibition) (NN:[889..898] mechanism))) (PP (IN:[899..903] with) (NP (NP (DT:[904..905] a) (NN:[907..909] Ki)) (PP (IN:[910..912] of) (NP (CD:[913..916] 100) (NN:[917..923] microM))))))) (.:[923..924] .))) ;sentence 9 Span:925..1058 ;Fluvoxamine, a new antidepressant, was shown to be a potent mixed-type ;inhibitor of methadone N-demethylation with a Ki of 7 microM. ;[925..936]:substance:"Fluvoxamine" ;[944..958]:substance:"antidepressant" ;[997..1006]:substance:"inhibitor" ;[1010..1019]:substance:"methadone" ;[1043..1045]:quantitative-name:"Ki" ;[1049..1050]:quantitative-value:"7" ;[1051..1057]:quantitative-units:"microM" (SENT (S (NP-SBJ-1 (NP (NN:[925..936] Fluvoxamine)) (,:[936..937] ,) (NP (DT:[938..939] a) (JJ:[940..943] new) (NN:[944..958] antidepressant))) (,:[958..959] ,) (VP (VBD:[960..963] was) (VP (VBN:[964..969] shown) (S (NP-SBJ-1 (-NONE-:[969..969] *)) (VP (TO:[970..972] to) (VP (VB:[973..975] be) (NP-PRD (NP (DT:[976..977] a) (JJ:[978..984] potent) (NML (VBN:[986..991] mixed) (HYPH:[991..992] -) (NN:[992..996] type)) (NN:[997..1006] inhibitor)) (PP (IN:[1007..1009] of) (NP (NN:[1010..1019] methadone) (NN:[1020..1035] N-demethylation))) (PP (IN:[1036..1040] with) (NP (NP (DT:[1041..1042] a) (NN:[1043..1045] Ki)) (PP (IN:[1046..1048] of) (NP (CD:[1049..1050] 7) (NN:[1051..1057] microM))))))))))) (.:[1057..1058] .))) ;sentence 10 Span:1060..1174 ;Finally, methadone appears to be a mixed-type inhibitor and not a suicide ;inhibitor of cytochrome P450 3A family. ;[1069..1078]:substance:"methadone" ;[1106..1115]:substance:"inhibitor" ;[1135..1144]:substance:"inhibitor" ;[1148..1166]:cyp450:"cytochrome P450 3A" (SENT (S (ADVP (RB:[1060..1067] Finally)) (,:[1067..1068] ,) (NP-SBJ (NN:[1069..1078] methadone)) (VP (VBZ:[1079..1086] appears) (S (NP-SBJ (-NONE-:[1086..1086] *)) (VP (TO:[1087..1089] to) (VP (VP (VB:[1090..1092] be) (NP-PRD (DT:[1093..1094] a) (NML (VBN:[1095..1100] mixed) (HYPH:[1100..1101] -) (NN:[1101..1105] type)) (NN:[1106..1115] inhibitor))) (CC:[1116..1119] and) (VP (RB:[1120..1123] not) (NP-PRD (NP (DT:[1124..1125] a) (NN:[1126..1133] suicide) (NN:[1135..1144] inhibitor)) (PP (IN:[1145..1147] of) (NP (NML (NML (NN:[1148..1158] cytochrome) (NN:[1159..1163] P450)) (NN:[1164..1166] 3A)) (NN:[1167..1173] family))))))))) (.:[1173..1174] .))) ;sentence 11 Span:1175..1388 ;Accordingly, caution should be advised in the clinical use of methadone when ;other drugs are administered that are able to induce or inhibit P450 3A4, ;such as rifampicin or nifedipine, diazepam and fluvoxamine. ;[1238..1247]:substance:"methadone" ;[1259..1264]:substance:"drugs" ;[1318..1326]:cyp450:"P450 3A4" ;[1336..1346]:substance:"rifampicin" ;[1350..1360]:substance:"nifedipine" ;[1362..1370]:substance:"diazepam" ;[1376..1387]:substance:"fluvoxamine" (SENT (S (ADVP (RB:[1175..1186] Accordingly)) (,:[1186..1187] ,) (NP-SBJ-4 (NN:[1188..1195] caution)) (VP (MD:[1196..1202] should) (VP (VB:[1203..1205] be) (VP (VBN:[1206..1213] advised) (NP-4 (-NONE-:[1213..1213] *)) (PP (IN:[1215..1217] in) (NP (NP (DT:[1218..1221] the) (JJ:[1222..1230] clinical) (NN:[1231..1234] use)) (PP (IN:[1235..1237] of) (NP (NN:[1238..1247] methadone))))) (SBAR-TMP (WHADVP-3 (WRB:[1248..1252] when)) (S (NP-SBJ-5 (NP (NP (JJ:[1253..1258] other) (NNS:[1259..1264] drugs)) (SBAR-6 (-NONE-:[1264..1264] *ICH*))) (PP-1 (-NONE-:[1264..1264] *ICH*))) (VP (VBP:[1265..1268] are) (VP (VBN:[1269..1281] administered) (NP-5 (-NONE-:[1281..1281] *)) (SBAR-6 (WHNP-2 (WDT:[1282..1286] that)) (S (NP-SBJ-2 (-NONE-:[1286..1286] *T*)) (VP (VBP:[1287..1290] are) (ADJP-PRD (JJ:[1291..1295] able) (S (NP-SBJ (-NONE-:[1295..1295] *)) (VP (TO:[1297..1299] to) (VP (VB:[1300..1306] induce) (CC:[1307..1309] or) (VB:[1310..1317] inhibit) (NP (NN:[1318..1322] P450) (NN:[1323..1326] 3A4))))))))) (,:[1326..1327] ,) (PP-1 (JJ:[1328..1332] such) (IN:[1333..1335] as) (NP (NP (NN:[1336..1346] rifampicin)) (CC:[1347..1349] or) (NP (NN:[1350..1360] nifedipine) (,:[1360..1361] ,) (NN:[1362..1370] diazepam) (CC:[1371..1374] and) (NN:[1376..1387] fluvoxamine)))) (ADVP-TMP-3 (-NONE-:[1387..1387] *T*))))))))) (.:[1387..1388] .))) ;section 12 Span:1392..1436 ;PMID: 9020195 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1392..1396] PMID) (::[1396..1397] :) (CD:[1398..1405] 9020195) (NN:[1406..1407] -LSB-) (NNP:[1407..1413] PubMed) (::[1414..1415] -) (NN:[1416..1423] indexed) (IN:[1424..1427] for) (NNP:[1428..1436] MEDLINE-RSB-)))