;PMID: 12141399 ;source_file_1866.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..39] = [t:0..39] ;1)sentence:[e:45..113] = [t:45..113] ;2)section:[e:117..145] = [t:117..145] ;3)section:[e:149..263] = [t:149..263] ;4)sentence:[e:267..454] = [t:267..454] ;5)sentence:[e:455..627] = [t:455..627] ;6)sentence:[e:628..730] = [t:628..730] ;7)sentence:[e:731..809] = [t:731..809] ;8)sentence:[e:810..944] = [t:810..944] ;9)sentence:[e:945..1107] = [t:945..1107] ;10)sentence:[e:1108..1271] = [t:1108..1271] ;11)sentence:[e:1272..1455] = [t:1272..1455] ;12)sentence:[e:1456..1563] = [t:1456..1563] ;13)sentence:[e:1564..1669] = [t:1564..1669] ;14)section:[e:1673..1718] = [t:1673..1718] ;section 0 Span:0..39 ;Hum Exp Toxicol. 2002 May;21(5):273-80. (SEC (FRAG (NNP:[0..3] Hum) (NNP:[4..7] Exp) (NNP:[8..15] Toxicol) (.:[15..16] .) ('':[17..21] 2002) (NNP:[22..25] May) (CD:[25..28] ;21) (-LRB-:[28..29] -LRB-) (CD:[29..30] 5) (-RRB-:[30..31] -RRB-) (CD:[31..35] :273) (::[35..36] -) (CD:[36..38] 80) (.:[38..39] .))) ;sentence 1 Span:45..113 ;Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse. ;[45..60]:substance:"Methylphenidate" ;[70..85]:cyp450:"cytochrome P450" (SENT (S-HLN (NP-SBJ (NN:[45..60] Methylphenidate)) (VP (VBZ:[61..69] inhibits) (NP (NN:[70..80] cytochrome) (NN:[81..85] P450)) (PP-LOC (IN:[86..88] in) (NP (DT:[89..92] the) (JJ:[93..98] Swiss) (NNP:[99..106] Webster) (NN:[107..112] mouse)))) (.:[112..113] .))) ;section 2 Span:117..145 ;Le Nedelec MJ, Rosengren RJ. (SEC (FRAG (NNP:[117..119] Le) (NNP:[120..127] Nedelec) (NNP:[128..130] MJ) (,:[130..131] ,) (NNP:[132..141] Rosengren) (NNP:[142..145] RJ.))) ;section 3 Span:149..263 ;Department of Pharmacology and Toxicology, School of Medical Sciences, ;University of Otago, Dunedin, New Zealand. (SEC (FRAG (NNP:[149..159] Department) (IN:[160..162] of) (NNP:[163..175] Pharmacology) (CC:[176..179] and) (NNP:[180..190] Toxicology) (,:[190..191] ,) (NNP:[192..198] School) (IN:[199..201] of) (NNP:[202..209] Medical) (NNP:[210..218] Sciences) (,:[218..219] ,) (NNP:[221..231] University) (IN:[232..234] of) (NNP:[235..240] Otago) (,:[240..241] ,) (NNP:[242..249] Dunedin) (,:[249..250] ,) (NNP:[251..254] New) (NNP:[255..262] Zealand) (.:[262..263] .))) ;sentence 4 Span:267..454 ;Drug interactions have previously been reported following the ;co-administration of methylphenidate (MPH) and drugs metabolized by the ;cytochrome P450 (CYP450) system such as imipramine. ;[267..271]:substance:"Drug" ;[351..366]:substance:"methylphenidate" ;[368..371]:substance:"MPH" ;[377..382]:substance:"drugs" ;[402..417]:cyp450:"cytochrome P450" ;[419..425]:cyp450:"CYP450" ;[443..453]:substance:"imipramine" (SENT (S (NP-SBJ-1 (NN:[267..271] Drug) (NNS:[272..284] interactions)) (VP (VBP:[285..289] have) (ADVP-TMP (RB:[290..300] previously)) (VP (VBN:[301..305] been) (VP (VBN:[306..314] reported) (NP-1 (-NONE-:[314..314] *)) (S-ADV (NP-SBJ (-NONE-:[314..314] *)) (VP (VBG:[315..324] following) (NP (NP (DT:[325..328] the) (AFX:[329..331] co) (HYPH:[331..332] -) (NN:[332..346] administration)) (PP (IN:[348..350] of) (NP (NP (NP (NN:[351..366] methylphenidate)) (NP (-LRB-:[367..368] -LRB-) (NN:[368..371] MPH) (-RRB-:[371..372] -RRB-))) (CC:[373..376] and) (NP (NP (NP (NNS:[377..382] drugs)) (VP (VBN:[383..394] metabolized) (NP (-NONE-:[394..394] *)) (PP (IN:[395..397] by) (NP-LGS (DT:[398..401] the) (NML (NML (NN:[402..412] cytochrome) (NN:[413..417] P450)) (NML (-LRB-:[418..419] -LRB-) (NN:[419..425] CYP450) (-RRB-:[425..426] -RRB-))) (NN:[428..434] system))))) (PP (JJ:[435..439] such) (IN:[440..442] as) (NP (NN:[443..453] imipramine)))))))))))) (.:[453..454] .))) ;sentence 5 Span:455..627 ;Therefore, this study used the Swiss Webster mouse to determine the effect ;of MPH on CYP450 isozymes likely to be important in the interaction between ;MPH and imipramine. ;[534..537]:substance:"MPH" ;[541..556]:cyp450:"CYP450 isozymes" ;[608..611]:substance:"MPH" ;[616..626]:substance:"imipramine" (SENT (S (ADVP (RB:[455..464] Therefore)) (,:[464..465] ,) (NP-SBJ (DT:[466..470] this) (NN:[471..476] study)) (VP (VBD:[477..481] used) (NP (DT:[482..485] the) (JJ:[486..491] Swiss) (NNP:[492..499] Webster) (NN:[500..505] mouse)) (S-PRP (NP-SBJ (-NONE-:[505..505] *)) (VP (TO:[506..508] to) (VP (VB:[510..519] determine) (NP (NP (DT:[520..523] the) (NN:[524..530] effect)) (PP (IN:[531..533] of) (NP (NN:[534..537] MPH))) (PP (IN:[538..540] on) (NP (NP-1 (NN:[541..547] CYP450) (NNS:[548..556] isozymes)) (ADJP (JJ:[557..563] likely) (S (NP-SBJ-1 (-NONE-:[563..563] *)) (VP (TO:[564..566] to) (VP (VB:[567..569] be) (ADJP-PRD (JJ:[570..579] important) (PP (IN:[580..582] in) (NP (NP (DT:[583..586] the) (NN:[588..599] interaction)) (PP (IN:[600..607] between) (NP (NP (NN:[608..611] MPH)) (CC:[612..615] and) (NP (NN:[616..626] imipramine)))))))))))))))))) (.:[626..627] .))) ;sentence 6 Span:628..730 ;Single high doses of MPH (25, 50 and 100 mg/kg, i.p.) were administered to ;simulate the abuse of MPH. ;[649..652]:substance:"MPH" ;[654..656]:quantitative-value:"25" ;[658..660]:quantitative-value:"50" ;[665..668]:quantitative-value:"100" ;[670..675]:quantitative-units:"mg/kg" ;[726..729]:substance:"MPH" (SENT (S (NP-SBJ-2 (NP (NP (JJ:[628..634] Single) (JJ:[635..639] high) (NNS:[640..645] doses)) (PP (IN:[646..648] of) (NP (NN:[649..652] MPH)))) (PRN (-LRB-:[653..654] -LRB-) (FRAG (NP (NP (NP (CD:[654..656] 25) (NML-1 (-NONE-:[656..656] *P*)) (PP-3 (-NONE-:[656..656] *RNR*))) (,:[656..657] ,) (NP (CD:[658..660] 50) (NML-1 (-NONE-:[660..660] *P*)) (PP-3 (-NONE-:[660..660] *RNR*))) (CC:[661..664] and) (NP (CD:[665..668] 100) (NML-1 (NN:[670..672] mg)) (PP-3 (-NONE-:[672..672] *RNR*)))) (PP-3 (SYM:[672..673] /) (NP (NN:[673..675] kg)))) (,:[675..676] ,) (ADVP (RB:[677..681] i.p.))) (-RRB-:[681..682] -RRB-))) (VP (VBD:[683..687] were) (VP (VBN:[688..700] administered) (NP-2 (-NONE-:[700..700] *)) (S-PRP (NP-SBJ (-NONE-:[700..700] *)) (VP (TO:[701..703] to) (VP (VB:[704..712] simulate) (NP (NP (DT:[713..716] the) (NN:[717..722] abuse)) (PP (IN:[723..725] of) (NP (NN:[726..729] MPH))))))))) (.:[729..730] .))) ;sentence 7 Span:731..809 ;Under these conditions, MPH decreased total hepatic CYP450 to 50% of ;control. ;[756..759]:substance:"MPH" ;[784..790]:cyp450:"CYP450" ;[794..797]:quantitative-value:"50%" (SENT (S (PP (IN:[731..736] Under) (NP (DT:[737..742] these) (NNS:[744..754] conditions))) (,:[754..755] ,) (NP-SBJ (NN:[756..759] MPH)) (VP (VBD:[760..769] decreased) (NP (JJ:[770..775] total) (JJ:[776..783] hepatic) (NN:[784..790] CYP450)) (PP-EXT (TO:[791..793] to) (NP (NP (CD:[794..796] 50) (NN:[796..797] %)) (PP (IN:[798..800] of) (NP (NN:[801..808] control)))))) (.:[808..809] .))) ;sentence 8 Span:810..944 ;Additionally, MPH inhibited the catalytic activity of CYP1A and CYP2E1 by ;50%, and decreased the polypeptide levels of CYP3A by 30%. ;[825..828]:substance:"MPH" ;[865..870]:cyp450:"CYP1A" ;[875..881]:cyp450:"CYP2E1" ;[885..888]:quantitative-value:"50%" ;[931..936]:cyp450:"CYP3A" ;[940..943]:quantitative-value:"30%" (SENT (S (ADVP (RB:[810..822] Additionally)) (,:[822..823] ,) (NP-SBJ (NN:[825..828] MPH)) (VP (VP (VBD:[829..838] inhibited) (NP (NP (DT:[839..842] the) (JJ:[843..852] catalytic) (NN:[853..861] activity)) (PP (IN:[862..864] of) (NP (NN:[865..870] CYP1A) (CC:[871..874] and) (NN:[875..881] CYP2E1)))) (PP-EXT (IN:[882..884] by) (NP (CD:[885..887] 50) (NN:[887..888] %)))) (,:[888..889] ,) (CC:[890..893] and) (VP (VBD:[894..903] decreased) (NP (NP (DT:[905..908] the) (NN:[909..920] polypeptide) (NNS:[921..927] levels)) (PP (IN:[928..930] of) (NP (NN:[931..936] CYP3A)))) (PP-EXT (IN:[937..939] by) (NP (CD:[940..942] 30) (NN:[942..943] %))))) (.:[943..944] .))) ;sentence 9 Span:945..1107 ;In a second study designed to simulate more closely therapeutic use, MPH was ;administered orally for two weeks at 10-fold lower doses (2.5, 5 and 10 ;mg/kg/day). ;[1015..1018]:substance:"MPH" ;[1047..1050]:quantitative-value:"two" ;[1051..1056]:quantitative-units:"weeks" ;[1061..1074]:quantitative-value:"10-fold lower" ;[1082..1085]:quantitative-value:"2.5" ;[1087..1088]:quantitative-value:"5" ;[1093..1095]:quantitative-value:"10" ;[1096..1105]:quantitative-units:"mg/kg/day" (SENT (S (PP (IN:[945..947] In) (NP (NP (DT:[948..949] a) (JJ:[950..956] second) (NN:[957..962] study)) (VP (VBN:[963..971] designed) (S (NP-SBJ (-NONE-:[971..971] *)) (VP (TO:[972..974] to) (VP (VB:[975..983] simulate) (NP (ADJP (ADVP (RBR:[985..989] more) (RB:[990..997] closely)) (JJ:[998..1009] therapeutic)) (NN:[1010..1013] use)))))))) (,:[1013..1014] ,) (NP-SBJ-3 (NN:[1015..1018] MPH)) (VP (VBD:[1019..1022] was) (VP (VBN:[1023..1035] administered) (NP-3 (-NONE-:[1035..1035] *)) (ADVP (RB:[1036..1042] orally)) (PP-TMP (IN:[1043..1046] for) (NP (CD:[1047..1050] two) (NNS:[1051..1056] weeks))) (PP (IN:[1057..1059] at) (NP (NP (ADJP (ADJP-EXT (CD:[1061..1063] 10) (HYPH:[1063..1064] -) (RB:[1064..1068] fold)) (JJR:[1069..1074] lower)) (NNS:[1075..1080] doses)) (PP (-LRB-:[1081..1082] -LRB-) (NP (NP (NP (CD:[1082..1085] 2.5) (NML-1 (-NONE-:[1085..1085] *P*))) (,:[1085..1086] ,) (NP (CD:[1087..1088] 5) (NML-1 (-NONE-:[1088..1088] *P*))) (CC:[1089..1092] and) (NP (CD:[1093..1095] 10) (NML-1 (NN:[1096..1098] mg)))) (PP (SYM:[1098..1099] /) (NP (NN:[1099..1101] kg))) (PP (SYM:[1101..1102] /) (NP (NN:[1102..1105] day)))) (-RRB-:[1105..1106] -RRB-)))))) (.:[1106..1107] .))) ;sentence 10 Span:1108..1271 ;MPH decreased total hepatic CYP450 at both 5 and 10 mg/ kg/day (0.96 +/- ;0.01 and 0.96 +/- 0.06 nmol/mg versus 1.34 +/- 0.01 nmol/mg for saline ;control, P<0.05). ;[1108..1111]:substance:"MPH" ;[1137..1143]:cyp450:"CYP450" ;[1152..1153]:quantitative-value:"5" ;[1158..1160]:quantitative-value:"10" ;[1161..1171]:quantitative-units:"mg/ kg/day" ;[1173..1186]:quantitative-value:"0.96 +/- 0.01" ;[1191..1204]:quantitative-value:"0.96 +/- 0.06" ;[1205..1212]:quantitative-units:"nmol/mg" ;[1221..1234]:quantitative-value:"1.34 +/- 0.01" ;[1235..1242]:quantitative-units:"nmol/mg" ;[1247..1253]:substance:"saline" ;[1254..1261]:substance:"control" (SENT (S (NP-SBJ (NN:[1108..1111] MPH)) (VP (VBD:[1112..1121] decreased) (NP (JJ:[1122..1127] total) (JJ:[1128..1135] hepatic) (NN:[1137..1143] CYP450)) (PP (IN:[1144..1146] at) (NP (NP (CC:[1147..1151] both) (NML (CD:[1152..1153] 5) (NML-2 (-NONE-:[1153..1153] *P*))) (CC:[1154..1157] and) (NML (CD:[1158..1160] 10) (NML-2 (NN:[1161..1163] mg)))) (PP (SYM:[1163..1164] /) (NP (NN:[1165..1167] kg))) (PP (SYM:[1167..1168] /) (NP (NN:[1168..1171] day))))) (PP (-LRB-:[1172..1173] -LRB-) (FRAG (NP (NP (NP (NP (QP (CD:[1173..1177] 0.96) (SYM:[1178..1181] +/-) (CD:[1182..1186] 0.01)) (NML-1 (-NONE-:[1186..1186] *P*))) (CC:[1187..1190] and) (NP (QP (CD:[1191..1195] 0.96) (SYM:[1196..1199] +/-) (CD:[1200..1204] 0.06)) (NML-1 (NN:[1205..1209] nmol)))) (PP (SYM:[1209..1210] /) (NP (NN:[1210..1212] mg)))) (PP (IN:[1214..1220] versus) (NP (NP (NP (QP (CD:[1221..1225] 1.34) (SYM:[1226..1229] +/-) (CD:[1230..1234] 0.01)) (NN:[1235..1239] nmol)) (PP (SYM:[1239..1240] /) (NP (NN:[1240..1242] mg)))) (PP (IN:[1243..1246] for) (NP (NN:[1247..1253] saline) (NN:[1254..1261] control)))))) (,:[1261..1262] ,) (S (NP-SBJ (NN:[1263..1264] P)) (VP (SYM:[1264..1265] <) (NP (CD:[1265..1269] 0.05))))) (-RRB-:[1269..1270] -RRB-))) (.:[1270..1271] .))) ;sentence 11 Span:1272..1455 ;The catalytic activity and protein levels of CYP1A were diminished by up to ;50% of control, while catalytic activity and polypeptide levels for CYP2E1 ;and CYP3A remained unchanged. ;[1300..1307]:substance:"protein" ;[1318..1323]:cyp450:"CYP1A" ;[1349..1352]:quantitative-value:"50%" ;[1418..1424]:cyp450:"CYP2E1" ;[1429..1434]:cyp450:"CYP3A" (SENT (S (NP-SBJ-1 (NP (DT:[1272..1275] The) (NML (NML (JJ:[1276..1285] catalytic) (NN:[1286..1294] activity)) (CC:[1296..1299] and) (NML (NN:[1300..1307] protein) (NNS:[1308..1314] levels)))) (PP (IN:[1315..1317] of) (NP (NN:[1318..1323] CYP1A)))) (VP (VBD:[1324..1328] were) (VP (VBN:[1329..1339] diminished) (NP-1 (-NONE-:[1339..1339] *)) (PP (IN:[1340..1342] by) (NP-EXT (NP (QP (IN:[1343..1345] up) (TO:[1346..1348] to) (CD:[1349..1351] 50)) (NN:[1351..1352] %)) (PP (IN:[1353..1355] of) (NP (NN:[1356..1363] control))))) (,:[1363..1364] ,) (SBAR-ADV (IN:[1365..1370] while) (S (NP-SBJ (NP (NP (JJ:[1372..1381] catalytic) (NN:[1382..1390] activity)) (CC:[1391..1394] and) (NP (NN:[1395..1406] polypeptide) (NNS:[1407..1413] levels))) (PP (IN:[1414..1417] for) (NP (NN:[1418..1424] CYP2E1) (CC:[1425..1428] and) (NN:[1429..1434] CYP3A)))) (VP (VBD:[1435..1443] remained) (ADJP-PRD (JJ:[1445..1454] unchanged))))))) (.:[1454..1455] .))) ;sentence 12 Span:1456..1563 ;These results indicate that MPH inhibits the CYP450 system following both ;abuse and therapeutic scenarios. ;[1484..1487]:substance:"MPH" ;[1501..1507]:cyp450:"CYP450" (SENT (S (NP-SBJ (DT:[1456..1461] These) (NNS:[1462..1469] results)) (VP (VBP:[1470..1478] indicate) (SBAR (IN:[1479..1483] that) (S (NP-SBJ (NN:[1484..1487] MPH)) (VP (VBZ:[1488..1496] inhibits) (NP (DT:[1497..1500] the) (NN:[1501..1507] CYP450) (NN:[1508..1514] system)) (S-MNR (NP-SBJ (-NONE-:[1514..1514] *)) (VP (VBG:[1515..1524] following) (NP (CC:[1526..1530] both) (NML (NML (NN:[1531..1536] abuse) (NML-1 (-NONE-:[1536..1536] *P*))) (CC:[1537..1540] and) (NML (JJ:[1541..1552] therapeutic) (NML-1 (NNS:[1553..1562] scenarios))))))))))) (.:[1562..1563] .))) ;sentence 13 Span:1564..1669 ;However, this effect was dependent on both the isoform of CYP450 and the ;duration of MPH administration. ;[1612..1619]:cyp450:"isoform" ;[1623..1629]:cyp450:"CYP450" ;[1650..1653]:substance:"MPH" (SENT (S (ADVP (RB:[1564..1571] However)) (,:[1571..1572] ,) (NP-SBJ (DT:[1573..1577] this) (NN:[1578..1584] effect)) (VP (VBD:[1585..1588] was) (ADJP-PRD (JJ:[1589..1598] dependent) (PP (IN:[1599..1601] on) (NP (CC:[1602..1606] both) (NP (NP (DT:[1608..1611] the) (NN:[1612..1619] isoform)) (PP (IN:[1620..1622] of) (NP (NN:[1623..1629] CYP450)))) (CC:[1630..1633] and) (NP (NP (DT:[1634..1637] the) (NN:[1638..1646] duration)) (PP (IN:[1647..1649] of) (NP (NN:[1650..1653] MPH) (NN:[1654..1668] administration)))))))) (.:[1668..1669] .))) ;section 14 Span:1673..1718 ;PMID: 12141399 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1673..1677] PMID) (::[1677..1678] :) (CD:[1679..1687] 12141399) (NN:[1688..1689] -LSB-) (NNP:[1689..1695] PubMed) (::[1696..1697] -) (NN:[1698..1705] indexed) (IN:[1706..1709] for) (NNP:[1710..1718] MEDLINE-RSB-)))