;PMID: 9010637 ;source_file_1917.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..40] = [t:0..40] ;1)sentence:[e:46..186] = [t:46..186] ;2)section:[e:190..249] = [t:190..249] ;3)section:[e:253..337] = [t:253..337] ;4)sentence:[e:341..547] = [t:341..547] ;5)sentence:[e:548..683] = [t:548..683] ;6)sentence:[e:684..1117] = [t:684..1117] ;7)sentence:[e:1118..1411] = [t:1118..1411] ;8)sentence:[e:1412..1533] = [t:1412..1533] ;9)section:[e:1537..1581] = [t:1537..1581] ;section 0 Span:0..40 ;Drug Metab Dispos. 1997 Jan;25(1):110-5. (SEC (FRAG (NNP:[0..4] Drug) (NNP:[5..10] Metab) (NNP:[11..17] Dispos) (.:[17..18] .) (CD:[19..23] 1997) (CC:[24..31] Jan;25-LRB-) (CD:[31..32] 1) (-RRB-:[32..33] -RRB-) (::[33..34] :) (CD:[34..39] 110-5) (.:[39..40] .))) ;sentence 1 Span:46..186 ;Identification of cytochromes P450 involved in the human liver microsomal ;metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001). ;[64..80]:cyp450:"cytochromes P450" ;[139..153]:substance:"thromboxane A2" ;[154..163]:substance:"inhibitor" ;[164..175]:substance:"seratrodast" ;[177..184]:substance:"ABT-001" (SENT (NP-HLN (NP (NN:[46..60] Identification)) (PP (IN:[61..63] of) (NP (NP (NNS:[64..75] cytochromes) (NN:[76..80] P450)) (VP (VBN:[81..89] involved) (NP (-NONE-:[89..89] *)) (PP-CLR (IN:[90..92] in) (NP (NP (DT:[93..96] the) (JJ:[97..102] human) (NN:[103..108] liver) (JJ:[109..119] microsomal) (NN:[121..131] metabolism)) (PP (IN:[132..134] of) (NP (NP (DT:[135..138] the) (NML (NN:[139..150] thromboxane) (NN:[151..153] A2)) (NN:[154..163] inhibitor)) (NP (NN:[164..175] seratrodast) (PRN (-LRB-:[176..177] -LRB-) (NP (NN:[177..184] ABT-001)) (-RRB-:[184..185] -RRB-)))))))))) (.:[185..186] .))) ;section 2 Span:190..249 ;Kumar GN, Dubberke E, Rodrigues AD, Roberts E, Dennisen JF. (SEC (FRAG (NNP:[190..195] Kumar) (NNP:[196..198] GN) (,:[198..199] ,) (NNP:[200..208] Dubberke) (NNP:[209..210] E) (,:[210..211] ,) (NNP:[212..221] Rodrigues) (NNP:[222..224] AD) (,:[224..225] ,) (NNP:[226..233] Roberts) (NNP:[234..235] E) (,:[235..236] ,) (NNP:[237..245] Dennisen) (NNP:[246..249] JF.))) ;section 3 Span:253..337 ;Biotransformation Department, Abbott Laboratories, Abbott Park, IL ;60064-3500, USA. (SEC (FRAG (NNP:[253..270] Biotransformation) (NNP:[271..281] Department) (,:[281..282] ,) (NNP:[283..289] Abbott) (NNP:[290..302] Laboratories) (,:[302..303] ,) (NNP:[304..310] Abbott) (NNP:[311..315] Park) (,:[315..316] ,) (NNP:[317..319] IL) (CD:[320..325] 60064) (CD:[325..330] -3500) (,:[330..331] ,) (NNP:[333..336] USA) (.:[336..337] .))) ;sentence 4 Span:341..547 ;Seratrodast (ABT-001, AA-2414) undergoes cytochrome P450 (CYP)-dependent ;metabolism to a major (5-methylhydroxy seratrodast; 5-HOS) and a minor ;4'-hydroxy seratrodast metabolite in human liver microsomes. ;[341..352]:substance:"Seratrodast" ;[354..361]:substance:"ABT-001" ;[363..370]:substance:"AA-2414" ;[382..397]:cyp450:"cytochrome P450" ;[399..402]:cyp450:"CYP" ;[438..465]:substance:"5-methylhydroxy seratrodast" ;[467..472]:substance:"5-HOS" ;[487..520]:substance:"4'-hydroxy seratrodast metabolite" (SENT (S (NP-SBJ (NN:[341..352] Seratrodast) (PRN (-LRB-:[353..354] -LRB-) (NP (NN:[354..361] ABT-001) (,:[361..362] ,) (NN:[363..370] AA-2414)) (-RRB-:[370..371] -RRB-))) (VP (VBZ:[372..381] undergoes) (NP (NP (ADJP (NML (NML (NN:[382..392] cytochrome) (NN:[393..397] P450)) (NML (-LRB-:[398..399] -LRB-) (NN:[399..402] CYP) (-RRB-:[402..403] -RRB-))) (HYPH:[403..404] -) (JJ:[404..413] dependent)) (NN:[415..425] metabolism)) (PP (TO:[426..428] to) (NP (NP (DT:[429..430] a) (JJ:[431..436] major) (PRN (-LRB-:[437..438] -LRB-) (FRAG (NP (NN:[438..453] 5-methylhydroxy) (NN:[454..465] seratrodast)) (::[465..466] ;) (NP (NN:[467..472] 5-HOS))) (-RRB-:[472..473] -RRB-)) (NML-1 (-NONE-:[473..473] *P*))) (CC:[474..477] and) (NP (DT:[478..479] a) (JJ:[480..485] minor) (NN:[487..497] 4'-hydroxy) (NML-1 (NN:[498..509] seratrodast) (NN:[510..520] metabolite)))))) (PP-LOC (IN:[521..523] in) (NP (JJ:[524..529] human) (NN:[530..535] liver) (NNS:[536..546] microsomes)))) (.:[546..547] .))) ;sentence 5 Span:548..683 ;The mean apparent K(m) and Vmax for the formation of 5-HOS were 15.5 microM ;and 589.0 pmol 5-HOS formed/mg protein/min, respectively. ;[567..571]:quantitative-name:"K(m)" ;[576..580]:quantitative-name:"Vmax" ;[602..607]:substance:"5-HOS" ;[613..617]:quantitative-value:"15.5" ;[618..624]:quantitative-units:"microM" ;[629..634]:quantitative-value:"589.0" ;[635..668]:quantitative-units:"pmol 5-HOS formed/mg protein/min" (SENT (S (NP-SBJ (NP (DT:[548..551] The) (NML (NML (ADJP-3 (JJ:[552..556] mean)) (ADJP-2 (JJ:[557..565] apparent)) (NN:[567..571] K-LRB-m-RRB-)) (CC:[572..575] and) (NML (ADJP-3 (-NONE-:[575..575] *P*)) (ADJP-2 (-NONE-:[575..575] *P*)) (NN:[576..580] Vmax)))) (PP (IN:[581..584] for) (NP (NP (DT:[585..588] the) (NN:[589..598] formation)) (PP (IN:[599..601] of) (NP (NN:[602..607] 5-HOS)))))) (VP (VBD:[608..612] were) (NP-PRD (NP (NP (NP (NML (CD:[613..617] 15.5) (NN:[618..624] microM)) (NML-1 (-NONE-:[624..624] *P*))) (CC:[625..628] and) (NP (NML (CD:[629..634] 589.0) (NN:[635..639] pmol)) (NML-1 (NN:[640..645] 5-HOS)))) (VP (VBN:[647..653] formed) (NP (-NONE-:[653..653] *)))) (PP (SYM:[653..654] /) (NP (NP (NN:[654..656] mg)) (NP (NN:[657..664] protein)))) (PP (SYM:[664..665] /) (NP (NN:[665..668] min)))) (,:[668..669] ,) (ADVP (RB:[670..682] respectively))) (.:[682..683] .))) ;sentence 6 Span:684..1117 ;Chemical inhibition using isoform-selective CYP inhibitors, correlation of ;5-HOS formation with several isoform-specific CYP activities in a panel of ;liver microsomes, metabolism by microsomes derived from CYP cDNA-expressed ;B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-CYP ;antibodies indicated that 5-HOS formation is catalyzed by CYP3A and ;CYP2C9/10, with a minor contribution from CYP2C8 and CYP2C19. ;[710..717]:cyp450:"isoform" ;[729..732]:cyp450:"CYP" ;[733..743]:substance:"inhibitors" ;[760..765]:substance:"5-HOS" ;[789..796]:cyp450:"isoform" ;[806..809]:cyp450:"CYP" ;[893..901]:substance:"CYP cDNA" ;[961..968]:substance:"isoform" ;[978..997]:substance:"anti-CYP antibodies" ;[1013..1018]:substance:"5-HOS" ;[1046..1051]:cyp450:"CYP3A" ;[1056..1062]:cyp450:"CYP2C9" ;[1056..1061]...[1063..1065]:cyp450:"CYP2C"..."10" ;[1098..1104]:cyp450:"CYP2C8" ;[1109..1116]:cyp450:"CYP2C19" (SENT (S (NP-SBJ (NP (NP (JJ:[684..692] Chemical) (NN:[693..703] inhibition)) (VP (VBG:[704..709] using) (NP (ADJP (NN:[710..717] isoform) (HYPH:[717..718] -) (JJ:[718..727] selective)) (NN:[729..732] CYP) (NNS:[733..743] inhibitors)))) (,:[743..744] ,) (NP (NP (NN:[745..756] correlation)) (PP (IN:[757..759] of) (NP (NN:[760..765] 5-HOS) (NN:[766..775] formation))) (PP (IN:[776..780] with) (NP (NP (JJ:[781..788] several) (ADJP (NN:[789..796] isoform) (HYPH:[796..797] -) (JJ:[797..805] specific)) (NN:[806..809] CYP) (NNS:[811..821] activities)) (PP (IN:[822..824] in) (NP (NP (DT:[825..826] a) (NN:[827..832] panel)) (PP (IN:[833..835] of) (NP (NN:[836..841] liver) (NNS:[842..852] microsomes)))))))) (,:[852..853] ,) (NP (NP (NN:[854..864] metabolism)) (PP (IN:[865..867] by) (NP (NP (NNS:[868..878] microsomes)) (VP (VBN:[879..886] derived) (NP (-NONE-:[886..886] *)) (PP (IN:[887..891] from) (NP (NN:[893..896] CYP) (ADJP (NN:[897..901] cDNA) (HYPH:[901..902] -) (VBN:[902..911] expressed)) (JJ:[912..928] B-lymphoblastoid) (NNS:[929..934] cells))))))) (,:[934..935] ,) (CC:[936..939] and) (NP (NP (NN:[940..956] immunoinhibition)) (PP (IN:[957..959] by) (NP (ADJP (NN:[961..968] isoform) (HYPH:[968..969] -) (JJ:[969..977] specific)) (NML (AFX:[978..982] anti) (HYPH:[982..983] -) (NN:[983..986] CYP)) (NNS:[987..997] antibodies))))) (VP (VBD:[998..1007] indicated) (SBAR (IN:[1008..1012] that) (S (NP-SBJ-2 (NN:[1013..1018] 5-HOS) (NN:[1019..1028] formation)) (VP (VBZ:[1029..1031] is) (VP (VBN:[1032..1041] catalyzed) (NP-2 (-NONE-:[1041..1041] *)) (PP (IN:[1043..1045] by) (NP-LGS (NP (NN:[1046..1051] CYP3A)) (CC:[1052..1055] and) (NP (NP (NML-1 (NN:[1056..1061] CYP2C)) (CD:[1061..1062] 9)) (SYM:[1062..1063] /) (NP (NML-1 (-NONE-:[1063..1063] *P*)) (CD:[1063..1065] 10))))) (,:[1065..1066] ,) (PP-MNR (IN:[1067..1071] with) (NP (NP (DT:[1072..1073] a) (JJ:[1074..1079] minor) (NN:[1080..1092] contribution)) (PP (IN:[1093..1097] from) (NP (NN:[1098..1104] CYP2C8) (CC:[1105..1108] and) (NN:[1109..1116] CYP2C19)))))))))) (.:[1116..1117] .))) ;sentence 7 Span:1118..1411 ;At clinically relevant concentrations, seratrodast was found to inhibit ;tolbutamide methylhydroxylation (IC50 = 60 microM), (S)-mephenytoin ;4'-hydroxylation (IC50 = 50 microM), and coumarin 7-hydroxylation (IC60 = 95 ;microM), indicating the potential for significant clinical interactions. ;[1158..1169]:substance:"seratrodast" ;[1191..1223]:substance:"tolbutamide methylhydroxylation" ;[1225..1229]:quantitative-name:"IC50" ;[1232..1234]:quantitative-value:"60" ;[1235..1241]:quantitative-units:"microM" ;[1244..1259]:substance:"(S)-mephenytoin" ;[1278..1282]:quantitative-name:"IC50" ;[1286..1288]:quantitative-value:"50" ;[1289..1295]:quantitative-units:"microM" ;[1302..1310]:substance:"coumarin" ;[1328..1332]:quantitative-name:"IC60" ;[1335..1337]:quantitative-value:"95" ;[1338..1344]:quantitative-units:"microM" (SENT (S (PP (IN:[1118..1120] At) (NP (ADJP (RB:[1122..1132] clinically) (JJ:[1133..1141] relevant)) (NNS:[1142..1156] concentrations))) (,:[1156..1157] ,) (NP-SBJ-1 (NN:[1158..1169] seratrodast)) (VP (VBD:[1170..1173] was) (VP (VBN:[1174..1179] found) (S (NP-SBJ-1 (-NONE-:[1179..1179] *)) (VP (TO:[1180..1182] to) (VP (VB:[1183..1190] inhibit) (NP (NP (NN:[1191..1202] tolbutamide) (NN:[1204..1223] methylhydroxylation) (PRN (-LRB-:[1224..1225] -LRB-) (S (NP-SBJ (NN:[1225..1229] IC50)) (VP (SYM:[1230..1231] =) (NP (CD:[1232..1234] 60) (NN:[1235..1241] microM)))) (-RRB-:[1241..1242] -RRB-))) (,:[1242..1243] ,) (NP (NN:[1244..1259] -LRB-S-RRB--mephenytoin) (NN:[1260..1276] 4'-hydroxylation) (PRN (-LRB-:[1277..1278] -LRB-) (S (NP-SBJ (NN:[1278..1282] IC50)) (VP (SYM:[1283..1284] =) (NP (CD:[1286..1288] 50) (NN:[1289..1295] microM)))) (-RRB-:[1295..1296] -RRB-))) (,:[1296..1297] ,) (CC:[1298..1301] and) (NP (NN:[1302..1310] coumarin) (NN:[1311..1326] 7-hydroxylation) (PRN (-LRB-:[1327..1328] -LRB-) (S (NP-SBJ (NN:[1328..1332] IC60)) (VP (SYM:[1333..1334] =) (NP (CD:[1335..1337] 95) (NN:[1338..1344] microM)))) (-RRB-:[1344..1345] -RRB-)))) (,:[1345..1346] ,) (S-ADV (NP-SBJ (-NONE-:[1346..1346] *)) (VP (VBG:[1347..1357] indicating) (NP (NP (DT:[1358..1361] the) (NN:[1363..1372] potential)) (PP (IN:[1373..1376] for) (NP (JJ:[1377..1388] significant) (JJ:[1389..1397] clinical) (NNS:[1398..1410] interactions))))))))))) (.:[1410..1411] .))) ;sentence 8 Span:1412..1533 ;The inducers of CYP3A and/or CYP2C9 (e.g. rifampicin and phenytoin) are ;likely to alter the disposition of seratrodast. ;[1416..1424]:substance:"inducers" ;[1428..1433]:cyp450:"CYP3A" ;[1442..1448]:cyp450:"CYP2C9" ;[1455..1465]:substance:"rifampicin" ;[1470..1479]:substance:"phenytoin" ;[1521..1532]:substance:"seratrodast" (SENT (S (NP-SBJ-1 (NP (NP (DT:[1412..1415] The) (NNS:[1416..1424] inducers)) (PP (IN:[1425..1427] of) (NP (NN:[1428..1433] CYP3A) (CC:[1434..1440] and/or) (NN:[1442..1448] CYP2C9)))) (PRN (-LRB-:[1449..1450] -LRB-) (NP (ADVP (FW:[1450..1454] e.g.)) (NN:[1455..1465] rifampicin) (CC:[1466..1469] and) (NN:[1470..1479] phenytoin)) (-RRB-:[1479..1480] -RRB-))) (VP (VBP:[1481..1484] are) (ADJP-PRD (JJ:[1485..1491] likely) (S (NP-SBJ-1 (-NONE-:[1491..1491] *)) (VP (TO:[1492..1494] to) (VP (VB:[1495..1500] alter) (NP (NP (DT:[1501..1504] the) (NN:[1505..1516] disposition)) (PP (IN:[1517..1519] of) (NP (NN:[1521..1532] seratrodast))))))))) (.:[1532..1533] .))) ;section 9 Span:1537..1581 ;PMID: 9010637 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1537..1541] PMID) (::[1541..1542] :) (CD:[1543..1550] 9010637) (NN:[1551..1552] -LSB-) (NNP:[1552..1558] PubMed) (::[1559..1560] -) (NN:[1561..1568] indexed) (IN:[1569..1572] for) (NNP:[1573..1581] MEDLINE-RSB-)))