;PMID: 9143866 ;source_file_1787.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..38] = [t:0..38] ;1)sentence:[e:44..144] = [t:44..144] ;2)section:[e:148..163] = [t:148..163] ;3)section:[e:167..241] = [t:167..241] ;4)sentence:[e:245..255] = [t:245..255] ;5)sentence:[e:256..342] = [t:256..342] ;6)sentence:[e:343..481] = [t:343..481] ;7)sentence:[e:482..490] = [t:482..490] ;8)sentence:[e:491..620] = [t:491..620] ;9)sentence:[e:621..718] = [t:621..718] ;10)sentence:[e:719..998] = [t:719..998] ;11)sentence:[e:999..1174] = [t:999..1174] ;12)sentence:[e:1175..1346] = [t:1175..1346] ;13)sentence:[e:1347..1358] = [t:1347..1358] ;14)sentence:[e:1359..1740] = [t:1359..1740] ;15)section:[e:1744..1788] = [t:1744..1788] ;section 0 Span:0..38 ;Eur J Clin Pharmacol. 1997;52(1):41-7. (SEC (FRAG (NNP:[0..3] Eur) (NNP:[4..5] J) (NNP:[6..10] Clin) (NNP:[11..20] Pharmacol) (.:[20..21] .) (CD:[22..30] 1997;52-LRB-) (CD:[30..31] 1) (-RRB-:[31..32] -RRB-) (::[32..33] :) (CD:[33..35] 41) (HYPH:[35..36] -) (CD:[36..38] 7.))) ;sentence 1 Span:44..144 ;Different effects of inhibitors on the O- and N-demethylation of codeine in ;human liver microsomes. ;[65..75]:substance:"inhibitors" ;[109..116]:substance:"codeine" (SENT (NP-HLN (NP (JJ:[44..53] Different) (NNS:[54..61] effects)) (PP (IN:[62..64] of) (NP (NNS:[65..75] inhibitors))) (PP (IN:[76..78] on) (NP (NP (DT:[79..82] the) (NML (NN:[83..84] O) (HYPH:[84..85] -) (NML-1 (-NONE-:[85..85] *P*))) (CC:[86..89] and) (NML (NN:[90..91] N) (HYPH:[91..92] -) (NML-1 (NN:[92..105] demethylation)))) (PP (IN:[106..108] of) (NP (NN:[109..116] codeine))))) (PP-LOC (IN:[117..119] in) (NP (JJ:[121..126] human) (NN:[127..132] liver) (NNS:[133..143] microsomes))) (.:[143..144] .))) ;section 2 Span:148..163 ;Yue QY, Sawe J. (SEC (FRAG (NNP:[148..151] Yue) (NNP:[152..154] QY) (,:[154..155] ,) (NNP:[156..160] Sawe) (NNP:[161..163] J.))) ;section 3 Span:167..241 ;Department of Clinical Pharmacology, Huddinge University Hospital, Sweden. (SEC (FRAG (NNP:[167..177] Department) (IN:[178..180] of) (NNP:[181..189] Clinical) (NNP:[190..202] Pharmacology) (,:[202..203] ,) (NNP:[204..212] Huddinge) (NNP:[213..223] University) (NNP:[224..232] Hospital) (,:[232..233] ,) (NNP:[234..240] Sweden) (.:[240..241] .))) ;sentence 4 Span:245..255 ;OBJECTIVE: (SENT (NP (NN:[245..254] OBJECTIVE) (::[254..255] :))) ;sentence 5 Span:256..342 ;The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 ;respectively. ;[286..293]:substance:"codeine" ;[310..316]:cyp450:"CYP2D6" ;[322..328]:cyp450:"CYP3A4" (SENT (S (NP-SBJ-2 (NP (DT:[256..259] The) (NML (NML (NN:[260..261] O) (HYPH:[261..262] -) (NML-1 (-NONE-:[262..262] *P*))) (CC:[263..266] and) (NML (NN:[267..268] N) (HYPH:[268..269] -) (NML-1 (NN:[269..282] demethylation))))) (PP (IN:[283..285] of) (NP (NN:[286..293] codeine)))) (VP (VBZ:[294..296] is) (VP (VBN:[297..306] catalysed) (NP-2 (-NONE-:[306..306] *)) (PP (IN:[307..309] by) (NP-LGS (NN:[310..316] CYP2D6) (CC:[317..320] and) (NN:[322..328] CYP3A4))) (ADVP (RB:[329..341] respectively)))) (.:[341..342] .))) ;sentence 6 Span:343..481 ;The formation rates of morphine by O-demethylation and norcodeine by ;N-demethylation were studied in two sets of human liver microsomes. ;[366..374]:substance:"morphine" ;[399..409]:substance:"norcodeine" (SENT (S (NP-SBJ-1 (NP (DT:[343..346] The) (NN:[347..356] formation) (NNS:[357..362] rates)) (PP (IN:[363..365] of) (NP (NP (NP (NN:[366..374] morphine)) (PP (IN:[375..377] by) (NP (NN:[378..393] O-demethylation)))) (CC:[394..397] and) (NP (NP (NN:[399..409] norcodeine)) (PP (IN:[410..412] by) (NP (NN:[413..428] N-demethylation))))))) (VP (VBD:[429..433] were) (VP (VBN:[434..441] studied) (NP-1 (-NONE-:[441..441] *)) (PP-LOC (IN:[442..444] in) (NP (NP (CD:[445..448] two) (NNS:[449..453] sets)) (PP (IN:[454..456] of) (NP (JJ:[457..462] human) (NN:[463..468] liver) (NNS:[470..480] microsomes))))))) (.:[480..481] .))) ;sentence 7 Span:482..490 ;RESULTS: (SENT (NP (NNS:[482..489] RESULTS) (::[489..490] :))) ;sentence 8 Span:491..620 ;Relatively high K(m) values were found for both O- and N-demethylations, ;suggesting a low affinity to the corresponding enzymes. ;[507..511]:quantitative-name:"K(m)" ;[612..619]:substance:"enzymes" (SENT (S (NP-SBJ-2 (ADJP (RB:[491..501] Relatively) (JJ:[502..506] high)) (NN:[507..511] K-LRB-m-RRB-) (NNS:[512..518] values)) (VP (VBD:[519..523] were) (VP (VBN:[524..529] found) (NP-2 (-NONE-:[529..529] *)) (PP (IN:[530..533] for) (NP (CC:[534..538] both) (NP (NP (NN:[539..540] O) (HYPH:[540..541] -) (NML-1 (-NONE-:[541..541] *P*))) (CC:[542..545] and) (NP (NN:[547..548] N) (HYPH:[548..549] -) (NML-1 (NNS:[549..563] demethylations)))))) (,:[563..564] ,) (S-ADV (NP-SBJ (-NONE-:[564..564] *)) (VP (VBG:[565..575] suggesting) (NP (NP (DT:[576..577] a) (JJ:[578..581] low) (NN:[582..590] affinity)) (PP (TO:[591..593] to) (NP (DT:[594..597] the) (VBG:[598..611] corresponding) (NNS:[612..619] enzymes)))))))) (.:[619..620] .))) ;sentence 9 Span:621..718 ;The inhibitory effects of various drugs were found to be different for O- ;and N-demethylations. ;[656..661]:substance:"drugs" (SENT (S (NP-SBJ-2 (NP (DT:[621..624] The) (JJ:[626..636] inhibitory) (NNS:[637..644] effects)) (PP (IN:[645..647] of) (NP (JJ:[648..655] various) (NNS:[656..661] drugs)))) (VP (VBD:[662..666] were) (VP (VBN:[667..672] found) (S (NP-SBJ-2 (-NONE-:[672..672] *)) (VP (TO:[673..675] to) (VP (VB:[676..678] be) (ADJP-PRD (JJ:[679..688] different) (PP (IN:[689..692] for) (NP (NP (NN:[693..694] O) (HYPH:[694..695] -) (NML-1 (-NONE-:[695..695] *P*))) (CC:[696..699] and) (NP (NN:[701..702] N) (HYPH:[702..703] -) (NML-1 (NNS:[703..717] demethylations))))))))))) (.:[717..718] .))) ;sentence 10 Span:719..998 ;The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol ;inhibited the O-demethylation of codeine preferentially, while the ;substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were ;all strong inhibitors of the N-demethylation of codeine. ;[723..733]:substance:"substrates" ;[737..743]:cyp450:"CYP2D6" ;[752..764]:substance:"thioridazine" ;[766..779]:substance:"amitriptyline" ;[785..795]:substance:"metoprolol" ;[829..836]:substance:"codeine" ;[864..874]:substance:"substrates" ;[878..884]:cyp450:"CYP3A4" ;[893..907]:substance:"cyclosporine A" ;[909..918]:substance:"midazolam" ;[923..935]:substance:"erythromycin" ;[953..963]:substance:"inhibitors" ;[990..997]:substance:"codeine" (SENT (S (NP-SBJ (NP (DT:[719..722] The) (NNS:[723..733] substrates)) (PP (IN:[734..736] of) (NP (NN:[737..743] CYP2D6))) (PP (JJ:[744..748] such) (IN:[749..751] as) (NP (NN:[752..764] thioridazine) (,:[764..765] ,) (NN:[766..779] amitriptyline) (CC:[781..784] and) (NN:[785..795] metoprolol)))) (VP (VBD:[796..805] inhibited) (NP (NP (DT:[806..809] the) (NN:[810..825] O-demethylation)) (PP (IN:[826..828] of) (NP (NN:[829..836] codeine)))) (ADVP (RB:[837..851] preferentially)) (,:[851..852] ,) (SBAR-ADV (IN:[853..858] while) (S (NP-SBJ (NP (DT:[860..863] the) (NNS:[864..874] substrates)) (PP (IN:[875..877] of) (NP (NN:[878..884] CYP3A4))) (PP (JJ:[885..889] such) (IN:[890..892] as) (NP (NP (NN:[893..905] cyclosporine) (NN:[906..907] A)) (,:[907..908] ,) (NP (NN:[909..918] midazolam)) (CC:[919..922] and) (NP (NN:[923..935] erythromycin))))) (VP (VBD:[936..940] were) (DT:[942..945] all) (NP-PRD (NP (JJ:[946..952] strong) (NNS:[953..963] inhibitors)) (PP (IN:[964..966] of) (NP (NP (DT:[967..970] the) (NN:[971..986] N-demethylation)) (PP (IN:[987..989] of) (NP (NN:[990..997] codeine)))))))))) (.:[997..998] .))) ;sentence 11 Span:999..1174 ;Quinidine and lignocaine, although they are substrates of CYP3A, showed ;preferential inhibition over the O-demethylation of codeine, suggesting a ;low affinity to the CYP3A. ;[999..1008]:substance:"Quinidine" ;[1014..1024]:substance:"lignocaine" ;[1044..1054]:substance:"substrates" ;[1058..1063]:cyp450:"CYP3A" ;[1125..1132]:substance:"codeine" ;[1168..1173]:cyp450:"CYP3A" (SENT (S (NP-SBJ (NN:[999..1008] Quinidine) (CC:[1009..1012] and) (NN:[1014..1024] lignocaine)) (,:[1024..1025] ,) (SBAR-ADV (IN:[1026..1034] although) (S (NP-SBJ (PRP:[1035..1039] they)) (VP (VBP:[1040..1043] are) (NP-PRD (NP (NNS:[1044..1054] substrates)) (PP (IN:[1055..1057] of) (NP (NN:[1058..1063] CYP3A))))))) (,:[1063..1064] ,) (VP (VBD:[1065..1071] showed) (NP (NP (JJ:[1072..1084] preferential) (NN:[1086..1096] inhibition)) (PP (IN:[1097..1101] over) (NP (NP (DT:[1102..1105] the) (NN:[1106..1121] O-demethylation)) (PP (IN:[1122..1124] of) (NP (NN:[1125..1132] codeine)))))) (,:[1132..1133] ,) (S-MNR (NP-SBJ (-NONE-:[1133..1133] *)) (VP (VBG:[1134..1144] suggesting) (NP (NP (DT:[1145..1146] a) (JJ:[1147..1150] low) (NN:[1151..1159] affinity)) (PP (TO:[1160..1162] to) (NP (DT:[1163..1166] the) (NN:[1168..1173] CYP3A))))))) (.:[1173..1174] .))) ;sentence 12 Span:1175..1346 ;Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 ;over CYP3A, while theophylline did not inhibit the O- or N-demethylation to ;a greater extent. ;[1175..1184]:substance:"Methadone" ;[1189..1207]:substance:"dextropropoxyphene" ;[1245..1251]:cyp450:"CYP2D6" ;[1257..1262]:cyp450:"CYP3A" ;[1270..1282]:substance:"theophylline" (SENT (S (NP-SBJ (NN:[1175..1184] Methadone) (CC:[1185..1188] and) (NN:[1189..1207] dextropropoxyphene)) (VP (VBD:[1208..1214] showed) (NP (NP (DT:[1215..1216] a) (JJ:[1217..1229] preferential) (NN:[1230..1240] inhibition)) (PP (IN:[1241..1243] of) (NP (NN:[1245..1251] CYP2D6))) (PP (IN:[1252..1256] over) (NP (NN:[1257..1262] CYP3A)))) (,:[1262..1263] ,) (SBAR-ADV (IN:[1264..1269] while) (S (NP-SBJ (NN:[1270..1282] theophylline)) (VP (VBD:[1283..1286] did) (RB:[1287..1290] not) (VP (VB:[1291..1298] inhibit) (NP (DT:[1299..1302] the) (NML (NML (NN:[1303..1304] O) (HYPH:[1304..1305] -) (NML-1 (-NONE-:[1305..1305] *P*))) (CC:[1306..1308] or) (NML (NN:[1309..1310] N) (HYPH:[1310..1311] -) (NML-1 (NN:[1311..1324] demethylation))))) (PP (TO:[1326..1328] to) (NP (DT:[1329..1330] a) (JJR:[1331..1338] greater) (NN:[1339..1345] extent)))))))) (.:[1345..1346] .))) ;sentence 13 Span:1347..1358 ;CONCLUSION: (SENT (NP (NN:[1347..1357] CONCLUSION) (::[1357..1358] :))) ;sentence 14 Span:1359..1740 ;It seems that there was a good correspondence between the capacity of drugs ;to inhibit the O- and N-demethylation of codeine in human liver microsomes ;and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in ;man, suggesting that this in vitro inhibition test may be a useful screen ;for drugs which interact with these two important drug-metabolising ;enzymes. ;[1430..1435]:substance:"drugs" ;[1477..1484]:substance:"codeine" ;[1545..1551]:cyp450:"CYP2D6" ;[1555..1561]:cyp450:"CYP3A4" ;[1667..1672]:substance:"drugs" ;[1714..1718]:substance:"drug" ;[1732..1739]:cyp450:"enzymes" (SENT (S (NP-SBJ (PRP:[1359..1361] It)) (VP (VBZ:[1362..1367] seems) (SBAR (IN:[1368..1372] that) (S (NP-SBJ (EX:[1373..1378] there)) (VP (VBD:[1379..1382] was) (NP-PRD (NP (DT:[1383..1384] a) (JJ:[1385..1389] good) (NN:[1390..1404] correspondence)) (PP (IN:[1406..1413] between) (NP (NP (NP (DT:[1414..1417] the) (NN:[1418..1426] capacity) (S-3 (-NONE-:[1426..1426] *ICH*))) (PP (IN:[1427..1429] of) (NP (NNS:[1430..1435] drugs))) (S-3 (NP-SBJ (-NONE-:[1435..1435] *)) (VP (TO:[1436..1438] to) (VP (VB:[1439..1446] inhibit) (NP (NP (DT:[1447..1450] the) (NML (NML (NN:[1451..1452] O) (HYPH:[1452..1453] -) (NML-2 (-NONE-:[1453..1453] *P*))) (CC:[1454..1457] and) (NML (NN:[1458..1459] N) (HYPH:[1459..1460] -) (NML-2 (NN:[1460..1473] demethylation))))) (PP (IN:[1474..1476] of) (NP (NN:[1477..1484] codeine))) (PP-LOC (IN:[1486..1488] in) (NP (JJ:[1489..1494] human) (NN:[1495..1500] liver) (NNS:[1501..1511] microsomes)))))))) (CC:[1512..1515] and) (NP (NP (PRP$:[1516..1521] their) (JJ:[1522..1530] apparent) (NN:[1531..1541] metabolism)) (PP (IN:[1542..1544] by) (NP (NP (NN:[1545..1551] CYP2D6) (CC:[1552..1554] or) (NN:[1555..1561] CYP3A4)) (,:[1561..1562] ,) (ADVP (RB:[1564..1576] respectively)))) (ADVP (FW:[1577..1579] in) (FW:[1580..1584] vivo)) (PP-LOC (IN:[1585..1587] in) (NP (NN:[1588..1591] man))))))) (,:[1591..1592] ,) (S-ADV (NP-SBJ (-NONE-:[1592..1592] *)) (VP (VBG:[1593..1603] suggesting) (SBAR (IN:[1604..1608] that) (S (NP-SBJ (DT:[1609..1613] this) (NML (FW:[1614..1616] in) (FW:[1617..1622] vitro)) (NN:[1623..1633] inhibition) (NN:[1634..1638] test)) (VP (MD:[1639..1642] may) (VP (VB:[1644..1646] be) (NP-PRD (NP (DT:[1647..1648] a) (JJ:[1649..1655] useful) (NN:[1656..1662] screen)) (PP (IN:[1663..1666] for) (NP (NP (NNS:[1667..1672] drugs)) (SBAR (WHNP-1 (WDT:[1673..1678] which)) (S (NP-SBJ-1 (-NONE-:[1678..1678] *T*)) (VP (VBP:[1679..1687] interact) (PP-CLR (IN:[1688..1692] with) (NP (DT:[1693..1698] these) (CD:[1699..1702] two) (JJ:[1703..1712] important) (ADJP (NN:[1714..1718] drug) (HYPH:[1718..1719] -) (VBG:[1719..1731] metabolising)) (NNS:[1732..1739] enzymes))))))))))))))))))) (.:[1739..1740] .))) ;section 15 Span:1744..1788 ;PMID: 9143866 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1744..1748] PMID) (::[1748..1749] :) (CD:[1750..1757] 9143866) (NN:[1758..1759] -LSB-) (NNP:[1759..1765] PubMed) (::[1766..1767] -) (NN:[1768..1775] indexed) (IN:[1776..1779] for) (NNP:[1780..1788] MEDLINE-RSB-)))