;PMID: 10711629 ;source_file_1869.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..40] = [t:0..40] ;1)sentence:[e:46..164] = [t:46..164] ;2)section:[e:168..219] = [t:168..219] ;3)section:[e:223..283] = [t:223..283] ;4)sentence:[e:287..423] = [t:287..423] ;5)sentence:[e:424..680] = [t:424..680] ;6)sentence:[e:682..755] = [t:682..755] ;7)sentence:[e:757..908] = [t:757..908] ;8)sentence:[e:910..1091] = [t:910..1091] ;9)sentence:[e:1092..1291] = [t:1092..1291] ;10)sentence:[e:1292..1475] = [t:1292..1475] ;11)sentence:[e:1476..1705] = [t:1476..1705] ;12)sentence:[e:1706..1845] = [t:1706..1845] ;13)section:[e:1849..1894] = [t:1849..1894] ;section 0 Span:0..40 ;J Biochem Mol Toxicol. 2000;14(3):140-7. (SEC (FRAG (NNP:[0..1] J) (NNP:[2..9] Biochem) (NNP:[10..13] Mol) (NNP:[14..21] Toxicol) (.:[21..22] .) (CD:[23..27] 2000) (::[27..28] ;) (CD:[28..30] 14) (-LRB-:[30..31] -LRB-) (CD:[31..32] 3) (-RRB-:[32..33] -RRB-) (::[33..34] :) (CD:[34..37] 140) (::[37..38] -) (CD:[38..40] 7.))) ;sentence 1 Span:46..164 ;Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 ;isozymes, and Hansen's disease patients. ;[60..71]:substance:"thalidomide" ;[106..132]:cyp450:"cytochrome P-450 isozymes" (SENT (NP-HLN (NP (NN:[46..56] Metabolism)) (PP (IN:[57..59] of) (NP (NN:[60..71] thalidomide))) (PP-LOC (IN:[72..74] in) (NP (NP (JJ:[75..80] human) (NNS:[81..91] microsomes)) (,:[91..92] ,) (NP (VBN:[93..99] cloned) (JJ:[100..105] human) (NML (NN:[106..116] cytochrome) (NN:[117..122] P-450)) (NNS:[124..132] isozymes)) (,:[132..133] ,) (CC:[134..137] and) (NP (NML (NP (NNP:[138..144] Hansen) (POS:[144..146] 's)) (NN:[147..154] disease)) (NNS:[155..163] patients)))) (.:[163..164] .))) ;section 2 Span:168..219 ;Teo SK, Sabourin PJ, O'Brien K, Kook KA, Thomas SD. (SEC (FRAG (NNP:[168..171] Teo) (NNP:[172..174] SK) (,:[174..175] ,) (NNP:[176..184] Sabourin) (NNP:[185..187] PJ) (,:[187..188] ,) (NNP:[189..196] O'Brien) (NNP:[197..199] K,) (NNP:[200..204] Kook) (NNP:[205..207] KA) (,:[207..208] ,) (NNP:[209..215] Thomas) (NNP:[216..218] SD) (.:[218..219] .))) ;section 3 Span:223..283 ;Celgene Corporation, Warren, NJ 07059, USA. steo@celgene.com (SEC (FRAG (NNP:[223..230] Celgene) (NNP:[231..242] Corporation) (,:[242..243] ,) (NNP:[244..250] Warren) (,:[250..251] ,) (NNP:[252..254] NJ) (CD:[255..260] 07059) (,:[260..261] ,) (NNP:[262..265] USA) (.:[265..266] .) ('':[267..283] steo@celgene.com))) ;sentence 4 Span:287..423 ;Previous in vitro studies in rat microsomal preparations suggested that ;thalidomide is metabolized by the cytochrome P450 system (CYP). ;[360..371]:substance:"thalidomide" ;[394..409]:cyp450:"cytochrome P450" ;[418..421]:cyp450:"CYP" (SENT (S (NP-SBJ (NP (JJ:[287..295] Previous) (ADJP (FW:[296..298] in) (FW:[299..304] vitro)) (NNS:[305..312] studies)) (PP-LOC (IN:[313..315] in) (NP (NN:[316..319] rat) (JJ:[320..330] microsomal) (NNS:[331..343] preparations)))) (VP (VBD:[344..353] suggested) (SBAR (IN:[354..358] that) (S (NP-SBJ-1 (NN:[360..371] thalidomide)) (VP (VBZ:[372..374] is) (VP (VBN:[375..386] metabolized) (NP-1 (-NONE-:[386..386] *)) (PP (IN:[387..389] by) (NP-LGS (NP (DT:[390..393] the) (NML (NN:[394..404] cytochrome) (NN:[405..409] P450)) (NN:[410..416] system)) (NP (-LRB-:[417..418] -LRB-) (NN:[418..421] CYP) (-RRB-:[421..422] -RRB-))))))))) (.:[422..423] .))) ;sentence 5 Span:424..680 ;In this study, we examined the extent of thalidomide metabolism by ;preparations of pooled human microsomes, microsomes containing cloned human ;CYP isozymes (CYPIA2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, ;CYP3A4), and Hansen's disease patients. ;[466..477]:substance:"thalidomide" ;[569..581]:cyp450:"CYP isozymes" ;[583..589]:cyp450:"CYPIA2" ;[591..597]:cyp450:"CYP2A6" ;[600..606]:cyp450:"CYP2B6" ;[608..614]:cyp450:"CYP2C9" ;[616..623]:cyp450:"CYP2C19" ;[625..631]:cyp450:"CYP2D6" ;[633..639]:cyp450:"CYP2E1" ;[641..647]:cyp450:"CYP3A4" (SENT (S (PP-LOC (IN:[424..426] In) (NP (DT:[427..431] this) (NN:[432..437] study))) (,:[437..438] ,) (NP-SBJ (PRP:[440..442] we)) (VP (VBD:[443..451] examined) (NP (NP (DT:[452..455] the) (NN:[456..462] extent)) (PP (IN:[463..465] of) (NP (NP (NN:[466..477] thalidomide) (NN:[478..488] metabolism)) (PP (IN:[489..491] by) (NP (NP (NNS:[492..504] preparations)) (PP (IN:[505..507] of) (NP (NP (VBN:[508..514] pooled) (JJ:[515..520] human) (NNS:[522..532] microsomes)) (,:[532..533] ,) (NP (NP (NNS:[534..544] microsomes)) (VP (VBG:[545..555] containing) (NP (NP (VBN:[556..562] cloned) (JJ:[563..568] human) (NN:[569..572] CYP) (NNS:[573..581] isozymes)) (PRN (-LRB-:[582..583] -LRB-) (NP (NN:[583..589] CYPIA2) (,:[589..590] ,) (NN:[591..597] CYP2A6) (,:[597..598] ,) (NN:[600..606] CYP2B6) (,:[606..607] ,) (NN:[608..614] CYP2C9) (,:[614..615] ,) (NN:[616..623] CYP2C19) (,:[623..624] ,) (NN:[625..631] CYP2D6) (,:[631..632] ,) (NN:[633..639] CYP2E1) (,:[639..640] ,) (NN:[641..647] CYP3A4)) (-RRB-:[647..648] -RRB-))))) (,:[648..649] ,) (CC:[650..653] and) (NP (NML (NP (NNP:[654..660] Hansen) (POS:[660..662] 's)) (NN:[663..670] disease)) (NNS:[671..679] patients)))))))))) (.:[679..680] .))) ;sentence 6 Span:682..755 ;Results indicated that thalidomide was a poor substrate for CYP isozymes. ;[705..716]:substance:"thalidomide" ;[728..737]:substance:"substrate" ;[742..754]:cyp450:"CYP isozymes" (SENT (S (NP-SBJ (NNS:[682..689] Results)) (VP (VBD:[690..699] indicated) (SBAR (IN:[700..704] that) (S (NP-SBJ (NN:[705..716] thalidomide)) (VP (VBD:[717..720] was) (NP-PRD (DT:[721..722] a) (JJ:[723..727] poor) (NN:[728..737] substrate)) (PP (IN:[738..741] for) (NP (NN:[742..745] CYP) (NNS:[746..754] isozymes))))))) (.:[754..755] .))) ;sentence 7 Span:757..908 ;Alteration of incubation buffer, pH, incubation time, and microsome and ;thalidomide concentrations did not increase the production of any ;metabolites. ;[790..792]:quantitative-name:"pH" ;[830..841]:substance:"thalidomide" ;[896..907]:substance:"metabolites" (SENT (S (NP-SBJ (NP (NN:[757..767] Alteration)) (PP (IN:[768..770] of) (NP (NP (NN:[771..781] incubation) (NN:[782..788] buffer)) (,:[788..789] ,) (NP (NN:[790..792] pH)) (,:[792..793] ,) (NP (NN:[794..804] incubation) (NN:[805..809] time)) (,:[809..810] ,) (CC:[811..814] and) (NP (NP (NN:[815..824] microsome) (NML-1 (-NONE-:[824..824] *P*))) (CC:[825..828] and) (NP (NN:[830..841] thalidomide) (NML-1 (NNS:[842..856] concentrations))))))) (VP (VBD:[857..860] did) (RB:[861..864] not) (VP (VB:[865..873] increase) (NP (NP (DT:[874..877] the) (NN:[878..888] production)) (PP (IN:[889..891] of) (NP (DT:[892..895] any) (NNS:[896..907] metabolites)))))) (.:[907..908] .))) ;sentence 8 Span:910..1091 ;Thalidomide also did not inhibit metabolism of CYP-specific substrates and ;therefore any interactions with other drugs that are metabolized by the same ;enzyme system are unlikely. ;[910..921]:substance:"Thalidomide" ;[957..960]:cyp450:"CYP" ;[970..980]:substance:"substrates" ;[1024..1029]:substance:"drugs" ;[1064..1070]:substance:"enzyme" (SENT (S (S (NP-SBJ (NN:[910..921] Thalidomide)) (ADVP (RB:[922..926] also)) (VP (VBD:[927..930] did) (RB:[931..934] not) (VP (VB:[935..942] inhibit) (NP (NP (NN:[943..953] metabolism)) (PP (IN:[954..956] of) (NP (ADJP (NN:[957..960] CYP) (HYPH:[960..961] -) (JJ:[961..969] specific)) (NNS:[970..980] substrates))))))) (CC:[981..984] and) (S (ADVP (RB:[986..995] therefore)) (NP-SBJ (NP (DT:[996..999] any) (NNS:[1000..1012] interactions)) (PP (IN:[1013..1017] with) (NP (NP (JJ:[1018..1023] other) (NNS:[1024..1029] drugs)) (SBAR (WHNP-1 (WDT:[1030..1034] that)) (S (NP-SBJ-1 (-NONE-:[1034..1034] *T*)) (VP (VBP:[1035..1038] are) (VP (VBN:[1039..1050] metabolized) (NP-1 (-NONE-:[1050..1050] *)) (PP (IN:[1051..1053] by) (NP-LGS (DT:[1054..1057] the) (JJ:[1058..1062] same) (NN:[1064..1070] enzyme) (NN:[1071..1077] system)))))))))) (VP (VBP:[1078..1081] are) (ADJP-PRD (JJ:[1082..1090] unlikely)))) (.:[1090..1091] .))) ;sentence 9 Span:1092..1291 ;Hansen's patients were given a single oral dose of thalidomide (400 mg), and ;their blood and urine were collected at time points up to 72 hours, ;processed, and analyzed by tandem mass spectrometry. ;[1144..1155]:substance:"thalidomide" ;[1157..1160]:quantitative-value:"400" ;[1161..1163]:quantitative-units:"mg" ;[1186..1191]:substance:"urine" ;[1229..1231]:quantitative-value:"72" ;[1232..1237]:quantitative-units:"hours" (SENT (S (S (NP-SBJ-1 (NP (NNP:[1092..1098] Hansen) (POS:[1098..1100] 's)) (NNS:[1101..1109] patients)) (VP (VBD:[1110..1114] were) (VP (VBN:[1115..1120] given) (NP-1 (-NONE-:[1120..1120] *)) (NP (NP (DT:[1121..1122] a) (JJ:[1123..1129] single) (JJ:[1130..1134] oral) (NN:[1135..1139] dose)) (PP (IN:[1140..1142] of) (NP (NN:[1144..1155] thalidomide))) (PRN (-LRB-:[1156..1157] -LRB-) (NP (CD:[1157..1160] 400) (NN:[1161..1163] mg)) (-RRB-:[1163..1164] -RRB-)))))) (,:[1164..1165] ,) (CC:[1166..1169] and) (S (NP-SBJ-2 (PRP$:[1170..1175] their) (NN:[1176..1181] blood) (CC:[1182..1185] and) (NN:[1186..1191] urine)) (VP (VBD:[1192..1196] were) (VP (VP (VBN:[1197..1206] collected) (NP-2 (-NONE-:[1206..1206] *)) (PP-TMP (IN:[1207..1209] at) (NP (NP (NN:[1210..1214] time) (NNS:[1215..1221] points)) (PP (IN:[1222..1224] up) (TO:[1226..1228] to) (NP (CD:[1229..1231] 72) (NNS:[1232..1237] hours)))))) (,:[1237..1238] ,) (VP (VBN:[1239..1248] processed) (NP-2 (-NONE-:[1248..1248] *))) (,:[1248..1249] ,) (CC:[1250..1253] and) (VP (VBN:[1254..1262] analyzed) (NP-2 (-NONE-:[1262..1262] *)) (PP-MNR (IN:[1263..1265] by) (NP (NN:[1266..1272] tandem) (NN:[1273..1277] mass) (NN:[1278..1290] spectrometry))))))) (.:[1290..1291] .))) ;sentence 10 Span:1292..1475 ;Although thalidomide was present in the plasma and urine, no metabolites ;were found in the plasma and very low amounts of the 5-OH thalidomide ;metabolite were present in the urine. ;[1302..1313]:substance:"thalidomide" ;[1344..1349]:substance:"urine" ;[1354..1365]:substance:"metabolites" ;[1420..1447]:substance:"5-OH thalidomide metabolite" ;[1469..1474]:substance:"urine" (SENT (S (S (SBAR-ADV (IN:[1292..1300] Although) (S (NP-SBJ (NN:[1302..1313] thalidomide)) (VP (VBD:[1314..1317] was) (ADJP-PRD (JJ:[1318..1325] present)) (PP-LOC (IN:[1326..1328] in) (NP (DT:[1329..1332] the) (NN:[1333..1339] plasma) (CC:[1340..1343] and) (NN:[1344..1349] urine)))))) (,:[1349..1350] ,) (NP-SBJ-1 (DT:[1351..1353] no) (NNS:[1354..1365] metabolites)) (VP (VBD:[1366..1370] were) (VP (VBN:[1371..1376] found) (NP-1 (-NONE-:[1376..1376] *)) (PP-LOC (IN:[1377..1379] in) (NP (DT:[1381..1384] the) (NN:[1385..1391] plasma)))))) (CC:[1392..1395] and) (S (NP-SBJ (NP (RB:[1396..1400] very) (JJ:[1401..1404] low) (NNS:[1405..1412] amounts)) (PP (IN:[1413..1415] of) (NP (DT:[1416..1419] the) (NN:[1420..1424] 5-OH) (NN:[1425..1436] thalidomide) (NN:[1437..1447] metabolite)))) (VP (VBD:[1448..1452] were) (ADJP-PRD (JJ:[1453..1460] present)) (PP-LOC (IN:[1462..1464] in) (NP (DT:[1465..1468] the) (NN:[1469..1474] urine))))) (.:[1474..1475] .))) ;sentence 11 Span:1476..1705 ;These results suggest that thalidomide does not undergo significant ;metabolism by human CYP and that clinically important interactions between ;thalidomide and drugs that are also metabolized by this enzyme system are ;unlikely. ;[1503..1514]:substance:"thalidomide" ;[1565..1568]:cyp450:"CYP" ;[1621..1632]:substance:"thalidomide" ;[1637..1642]:substance:"drugs" ;[1677..1683]:substance:"enzyme" (SENT (S (NP-SBJ (DT:[1476..1481] These) (NNS:[1482..1489] results)) (VP (VBP:[1490..1497] suggest) (SBAR (SBAR (IN:[1498..1502] that) (S (NP-SBJ (NN:[1503..1514] thalidomide)) (VP (VBZ:[1515..1519] does) (RB:[1520..1523] not) (VP (VB:[1524..1531] undergo) (NP (NP (JJ:[1533..1544] significant) (NN:[1545..1555] metabolism)) (PP (IN:[1556..1558] by) (NP (JJ:[1559..1564] human) (NN:[1565..1568] CYP)))))))) (CC:[1569..1572] and) (SBAR (IN:[1573..1577] that) (S (NP-SBJ (NP (ADJP (RB:[1578..1588] clinically) (JJ:[1589..1598] important)) (NNS:[1599..1611] interactions)) (PP (IN:[1613..1620] between) (NP (NP (NN:[1621..1632] thalidomide)) (CC:[1633..1636] and) (NP (NP (NNS:[1637..1642] drugs)) (SBAR (WHNP-1 (WDT:[1643..1647] that)) (S (NP-SBJ-1 (-NONE-:[1647..1647] *T*)) (VP (VBP:[1648..1651] are) (ADVP (RB:[1652..1656] also)) (VP (VBN:[1657..1668] metabolized) (NP-1 (-NONE-:[1668..1668] *)) (PP (IN:[1669..1671] by) (NP-LGS (DT:[1672..1676] this) (NN:[1677..1683] enzyme) (NN:[1684..1690] system))))))))))) (VP (VBP:[1692..1695] are) (ADJP-PRD (JJ:[1696..1704] unlikely))))))) (.:[1704..1705] .))) ;sentence 12 Span:1706..1845 ;The major route of thalidomide breakdown in humans and animals is through ;spontaneous hydrolysis with subsequent elimination in the urine. ;[1725..1736]:substance:"thalidomide" ;[1839..1844]:substance:"urine" (SENT (S (NP-SBJ (NP (DT:[1706..1709] The) (JJ:[1710..1715] major) (NN:[1716..1721] route)) (PP (IN:[1722..1724] of) (NP (NN:[1725..1736] thalidomide) (NN:[1737..1746] breakdown))) (PP-LOC (IN:[1747..1749] in) (NP (NNS:[1750..1756] humans) (CC:[1757..1760] and) (NNS:[1761..1768] animals)))) (VP (VBZ:[1769..1771] is) (PP-PRD (IN:[1773..1780] through) (NP (NP (JJ:[1781..1792] spontaneous) (NN:[1793..1803] hydrolysis)) (PP (IN:[1804..1808] with) (NP (NP (JJ:[1809..1819] subsequent) (NN:[1820..1831] elimination)) (PP-LOC (IN:[1832..1834] in) (NP (DT:[1835..1838] the) (NN:[1839..1844] urine)))))))) (.:[1844..1845] .))) ;section 13 Span:1849..1894 ;PMID: 10711629 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1849..1853] PMID) (::[1853..1854] :) (CD:[1855..1863] 10711629) (NN:[1864..1865] -LSB-) (NNP:[1865..1871] PubMed) (::[1872..1873] -) (NN:[1874..1881] indexed) (IN:[1882..1885] for) (NNP:[1886..1893] MEDLINE) (-RRB-:[1893..1894] -RSB-)))