;PMID: 9839089 ;source_file_1871.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..42] = [t:0..42] ;1)sentence:[e:48..122] = [t:48..122] ;2)section:[e:126..140] = [t:126..140] ;3)section:[e:144..223] = [t:144..223] ;4)sentence:[e:227..358] = [t:227..358] ;5)sentence:[e:359..457] = [t:359..457] ;6)sentence:[e:458..560] = [t:458..560] ;7)sentence:[e:561..722] = [t:561..722] ;8)sentence:[e:723..857] = [t:723..857] ;9)sentence:[e:858..1021] = [t:858..1021] ;10)sentence:[e:1022..1194] = [t:1022..1194] ;11)sentence:[e:1195..1341] = [t:1195..1341] ;12)sentence:[e:1342..1446] = [t:1342..1446] ;13)sentence:[e:1447..1637] = [t:1447..1637] ;14)sentence:[e:1638..1866] = [t:1638..1866] ;15)sentence:[e:1867..2111] = [t:1867..2111] ;16)sentence:[e:2112..2330] = [t:2112..2330] ;17)sentence:[e:2331..2586] = [t:2331..2586] ;18)sentence:[e:2587..2750] = [t:2587..2750] ;19)sentence:[e:2751..2889] = [t:2751..2889] ;20)section:[e:2893..2911] = [t:2893..2911] ;21)section:[e:2917..2923] = [t:2917..2923] ;22)section:[e:2929..2945] = [t:2929..2945] ;23)section:[e:2949..2993] = [t:2949..2993] ;section 0 Span:0..42 ;Clin Pharmacokinet. 1998 Nov;35(5):361-90. (SEC (FRAG (NNP:[0..4] Clin) (NNP:[5..18] Pharmacokinet) (.:[18..19] .) (CD:[20..24] 1998) (NNP:[25..28] Nov) (::[28..29] ;) (CD:[29..31] 35) (-LRB-:[31..32] -LRB-) (CD:[32..33] 5) (-RRB-:[33..34] -RRB-) (::[34..35] :) (CD:[35..38] 361) (HYPH:[38..39] -) (CD:[39..41] 90) (.:[41..42] .))) ;sentence 1 Span:48..122 ;Inhibition and induction of cytochrome P450 and the clinical implications. ;[76..91]:cyp450:"cytochrome P450" (SENT (NP-HLN (NP (NN:[48..58] Inhibition) (NP (CC:[59..62] and) (NN:[63..72] induction)) (PP (IN:[73..75] of) (NP (NN:[76..86] cytochrome) (NN:[87..91] P450)))) (CC:[92..95] and) (NP (DT:[96..99] the) (JJ:[100..108] clinical) (NNS:[109..121] implications)) (.:[121..122] .))) ;section 2 Span:126..140 ;Lin JH, Lu AY. (SEC (FRAG (NNP:[126..129] Lin) (NNP:[130..132] JH) (,:[132..133] ,) (NNP:[134..136] Lu) (NNP:[137..139] AY) (.:[139..140] .))) ;section 3 Span:144..223 ;Merck Research Laboratories, West Point, Pennsylvania, USA. ;jiunn_lin@merck.com (SEC (FRAG (NNP:[144..149] Merck) (NNP:[150..158] Research) (NNP:[159..171] Laboratories) (,:[171..172] ,) (NNP:[173..177] West) (NNP:[178..183] Point) (,:[183..184] ,) (NNP:[185..197] Pennsylvania) (,:[197..198] ,) (NNP:[199..202] USA) (.:[202..203] .) ('':[204..223] jiunn_lin@merck.com))) ;sentence 4 Span:227..358 ;The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an ; important role in the oxidative metabolism of drugs. ;[231..247]:cyp450:"cytochrome P450s" ;[249..253]:cyp450:"CYPs" ;[283..291]:cyp450:"isoforms" ;[352..357]:substance:"drugs" (SENT (S (NP-SBJ (NP (DT:[227..230] The) (NN:[231..241] cytochrome) (NNS:[242..247] P450s)) (NP (-LRB-:[248..249] -LRB-) (NNS:[249..253] CYPs) (-RRB-:[253..254] -RRB-))) (VP (VBP:[255..265] constitute) (NP (NP (DT:[266..267] a) (NN:[268..279] superfamily)) (PP (IN:[280..282] of) (NP (NP (NNS:[283..291] isoforms)) (SBAR (WHNP-1 (WDT:[292..296] that)) (S (NP-SBJ-1 (-NONE-:[296..296] *T*)) (VP (VBP:[297..301] play) (NP (DT:[302..304] an) (JJ:[306..315] important) (NN:[316..320] role)) (PP (IN:[321..323] in) (NP (NP (DT:[324..327] the) (JJ:[328..337] oxidative) (NN:[338..348] metabolism)) (PP (IN:[349..351] of) (NP (NNS:[352..357] drugs)))))))))))) (.:[357..358] .))) ;sentence 5 Span:359..457 ;Each CYP isoform possesses a characteristic broad spectrum of catalytic ;activities of substrates. ;[364..375]:cyp450:"CYP isoform" ;[446..456]:substance:"substrates" (SENT (S (NP-SBJ (DT:[359..363] Each) (NN:[364..367] CYP) (NN:[368..375] isoform)) (VP (VBZ:[376..385] possesses) (NP (NP (DT:[387..388] a) (JJ:[389..403] characteristic) (JJ:[404..409] broad) (NN:[410..418] spectrum)) (PP (IN:[419..421] of) (NP (NP (JJ:[422..431] catalytic) (NNS:[432..442] activities)) (PP (IN:[443..445] of) (NP (NNS:[446..456] substrates))))))) (.:[456..457] .))) ;sentence 6 Span:458..560 ;Whenever 2 or more drugs are administered concurrently, the possibility of ;drug interactions exists. ;[478..483]:substance:"drugs" ;[534..538]:substance:"drug" (SENT (S (SBAR-ADV (IN:[458..466] Whenever) (S (NP-SBJ-1 (QP (CD:[468..469] 2) (CC:[470..472] or) (JJR:[473..477] more)) (NNS:[478..483] drugs)) (VP (VBP:[484..487] are) (VP (VBN:[488..500] administered) (NP-1 (-NONE-:[500..500] *)) (ADVP-MNR (RB:[501..513] concurrently)))))) (,:[513..514] ,) (NP-SBJ (NP (DT:[515..518] the) (NN:[519..530] possibility)) (PP (IN:[531..533] of) (NP (NN:[534..538] drug) (NNS:[540..552] interactions)))) (VP (VBZ:[553..559] exists)) (.:[559..560] .))) ;sentence 7 Span:561..722 ;The ability of a single CYP to metabolise multiple substrates is responsible ;for a large number of documented drug interactions associated with CYP ;inhibition. ;[585..588]:cyp450:"CYP" ;[613..623]:substance:"substrates" ;[672..676]:substance:"drug" ;[707..710]:cyp450:"CYP" (SENT (S (NP-SBJ (NP (DT:[561..564] The) (NN:[565..572] ability) (S-1 (-NONE-:[572..572] *ICH*))) (PP (IN:[573..575] of) (NP (DT:[576..577] a) (JJ:[578..584] single) (NN:[585..588] CYP))) (S-1 (NP-SBJ (-NONE-:[588..588] *)) (VP (TO:[589..591] to) (VP (VB:[592..602] metabolise) (NP (JJ:[603..611] multiple) (NNS:[613..623] substrates)))))) (VP (VBZ:[624..626] is) (ADJP-PRD (JJ:[627..638] responsible) (PP (IN:[639..642] for) (NP (NP (DT:[643..644] a) (JJ:[645..650] large) (NN:[651..657] number)) (PP (IN:[658..660] of) (NP (NP (VBN:[661..671] documented) (NN:[672..676] drug) (NNS:[677..689] interactions)) (VP (VBN:[691..701] associated) (NP (-NONE-:[701..701] *)) (PP-CLR (IN:[702..706] with) (NP (NN:[707..710] CYP) (NN:[711..721] inhibition)))))))))) (.:[721..722] .))) ;sentence 8 Span:723..857 ;In addition, drug interactions can also occur as a result of the induction ;of several human CYPs following long term drug treatment. ;[736..740]:substance:"drug" ;[816..820]:cyp450:"CYPs" ;[841..845]:substance:"drug" (SENT (S (PP (IN:[723..725] In) (NP (NN:[726..734] addition))) (,:[734..735] ,) (NP-SBJ (NN:[736..740] drug) (NNS:[741..753] interactions)) (VP (MD:[754..757] can) (ADVP (RB:[758..762] also)) (VP (VB:[763..768] occur) (PP (IN:[769..771] as) (NP (NP (DT:[773..774] a) (NN:[775..781] result)) (PP (IN:[782..784] of) (NP (NP (DT:[785..788] the) (NN:[789..798] induction)) (PP (IN:[799..801] of) (NP (JJ:[802..809] several) (JJ:[810..815] human) (NNS:[816..820] CYPs))))))) (S (NP-SBJ (-NONE-:[820..820] *)) (VP (VBG:[821..830] following) (NP (NML (JJ:[831..835] long) (NN:[836..840] term)) (NN:[841..845] drug) (NN:[847..856] treatment)))))) (.:[856..857] .))) ;sentence 9 Span:858..1021 ;The mechanisms of CYP inhibition can be divided into 3 categories: (a) ;reversible inhibition; (b) quasi-irreversible inhibition; and (c) ;irreversible inhibition. ;[876..879]:cyp450:"CYP" (SENT (S (NP-SBJ-1 (NP (DT:[858..861] The) (NNS:[862..872] mechanisms)) (PP (IN:[873..875] of) (NP (NN:[876..879] CYP) (NN:[880..890] inhibition)))) (VP (MD:[891..894] can) (VP (VB:[895..897] be) (VP (VBN:[898..905] divided) (NP-1 (-NONE-:[905..905] *)) (PP-CLR (IN:[906..910] into) (NP (NP (CD:[911..912] 3) (NNS:[913..923] categories)) (::[923..924] :) (NP (NP (LST (LS:[926..929] -LRB-a-RRB-)) (JJ:[930..940] reversible) (NN:[941..951] inhibition)) (::[951..952] ;) (NP (LST (LS:[953..956] -LRB-b-RRB-)) (ADJP (AFX:[957..962] quasi) (HYPH:[962..963] -) (JJ:[963..975] irreversible)) (NN:[976..986] inhibition)) (::[986..987] ;) (CC:[988..991] and) (NP (LST (LS:[992..995] -LRB-c-RRB-)) (JJ:[997..1009] irreversible) (NN:[1010..1020] inhibition)))))))) (.:[1020..1021] .))) ;sentence 10 Span:1022..1194 ;In mechanistic terms, reversible interactions arise as a result of ;competition at the CYP active site and probably involve only the first step ;of the CYP catalytic cycle. ;[1109..1112]:cyp450:"CYP" ;[1174..1177]:cyp450:"CYP" (SENT (S (PP (IN:[1022..1024] In) (NP (JJ:[1025..1036] mechanistic) (NNS:[1037..1042] terms))) (,:[1042..1043] ,) (NP-SBJ (JJ:[1044..1054] reversible) (NNS:[1055..1067] interactions)) (VP (VP (VBP:[1068..1073] arise) (PP (IN:[1074..1076] as) (NP (NP (DT:[1078..1079] a) (NN:[1080..1086] result)) (PP (IN:[1087..1089] of) (NP (NP (NN:[1090..1101] competition)) (PP-LOC (IN:[1102..1104] at) (NP (DT:[1105..1108] the) (NN:[1109..1112] CYP) (JJ:[1113..1119] active) (NN:[1120..1124] site)))))))) (CC:[1125..1128] and) (VP (ADVP (RB:[1129..1137] probably)) (VBP:[1138..1145] involve) (NP (NP (RB:[1146..1150] only) (DT:[1151..1154] the) (JJ:[1156..1161] first) (NN:[1162..1166] step)) (PP (IN:[1167..1169] of) (NP (DT:[1170..1173] the) (NN:[1174..1177] CYP) (JJ:[1178..1187] catalytic) (NN:[1188..1193] cycle)))))) (.:[1193..1194] .))) ;sentence 11 Span:1195..1341 ;On the other hand, drugs that act during and subsequent to the oxygen ;transfer step are generally irreversible or quasi-irreversible inhibitors. ;[1214..1219]:substance:"drugs" ;[1259..1265]:substance:"oxygen" ;[1330..1340]:substance:"inhibitors" (SENT (S (PP (IN:[1195..1197] On) (NP (DT:[1198..1201] the) (JJ:[1202..1207] other) (NN:[1208..1212] hand))) (,:[1212..1213] ,) (NP-SBJ (NP (NNS:[1214..1219] drugs)) (SBAR (WHNP-3 (WDT:[1220..1224] that)) (S (NP-SBJ-3 (-NONE-:[1224..1224] *T*)) (VP (VBP:[1225..1228] act) (UCP-TMP (PP (IN:[1229..1235] during) (NP-2 (-NONE-:[1235..1235] *RNR*))) (CC:[1237..1240] and) (ADJP (JJ:[1241..1251] subsequent) (PP (TO:[1252..1254] to) (NP-2 (-NONE-:[1254..1254] *RNR*)))) (NP-2 (DT:[1255..1258] the) (NML (NN:[1259..1265] oxygen) (NN:[1266..1274] transfer)) (NN:[1275..1279] step))))))) (VP (VBP:[1280..1283] are) (ADVP (RB:[1284..1293] generally)) (NP-PRD (NP (JJ:[1294..1306] irreversible) (NML-1 (-NONE-:[1306..1306] *P*))) (CC:[1307..1309] or) (NP (ADJP (AFX:[1311..1316] quasi) (HYPH:[1316..1317] -) (JJ:[1317..1329] irreversible)) (NML-1 (NNS:[1330..1340] inhibitors))))) (.:[1340..1341] .))) ;sentence 12 Span:1342..1446 ;Irreversible and quasi-irreversible inhibition require at least one cycle of ;the CYP catalytic process. ;[1424..1427]:cyp450:"CYP" (SENT (S (NP-SBJ (NP (JJ:[1342..1354] Irreversible) (NML-1 (-NONE-:[1354..1354] *P*))) (CC:[1355..1358] and) (NP (ADJP (AFX:[1359..1364] quasi) (HYPH:[1364..1365] -) (JJ:[1365..1377] irreversible)) (NML-1 (NN:[1378..1388] inhibition)))) (VP (VBP:[1390..1397] require) (NP (NP (QP (IN:[1398..1400] at) (JJS:[1401..1406] least) (CD:[1407..1410] one)) (NN:[1411..1416] cycle)) (PP (IN:[1417..1419] of) (NP (DT:[1420..1423] the) (NN:[1424..1427] CYP) (JJ:[1428..1437] catalytic) (NN:[1438..1445] process))))) (.:[1445..1446] .))) ;sentence 13 Span:1447..1637 ;Because human liver samples and recombinant human CYPs are now readily ;available, in vitro systems have been used as screening tools to predict the ;potential for in vivo drug interaction. ;[1498..1502]:cyp450:"CYPs" ;[1619..1623]:substance:"drug" (SENT (S (SBAR-ADV (IN:[1447..1454] Because) (S (NP-SBJ (NP (JJ:[1455..1460] human) (NN:[1461..1466] liver) (NNS:[1468..1475] samples)) (CC:[1476..1479] and) (NP (JJ:[1480..1491] recombinant) (JJ:[1492..1497] human) (NNS:[1498..1502] CYPs))) (VP (VBP:[1503..1506] are) (ADVP-TMP (RB:[1507..1510] now)) (ADJP-PRD (RB:[1511..1518] readily) (JJ:[1519..1528] available))))) (,:[1528..1529] ,) (NP-SBJ-1 (ADJP (FW:[1530..1532] in) (FW:[1533..1538] vitro)) (NNS:[1539..1546] systems)) (VP (VBP:[1548..1552] have) (VP (VBN:[1553..1557] been) (VP (VBN:[1558..1562] used) (NP-1 (-NONE-:[1562..1562] *)) (PP (IN:[1563..1565] as) (NP (VBG:[1566..1575] screening) (NNS:[1576..1581] tools))) (S-PRP (NP-SBJ (-NONE-:[1581..1581] *)) (VP (TO:[1582..1584] to) (VP (VB:[1585..1592] predict) (NP (NP (DT:[1593..1596] the) (NN:[1597..1606] potential)) (PP (IN:[1607..1610] for) (NP (ADJP (FW:[1611..1613] in) (FW:[1614..1618] vivo)) (NN:[1619..1623] drug) (NN:[1625..1636] interaction)))))))))) (.:[1636..1637] .))) ;sentence 14 Span:1638..1866 ;Although it is easy to determine in vitro metabolic drug interactions, the ;proper interpretation and extrapolation of in vitro interaction data to in ;vivo situations require a good understanding of pharmacokinetic principles. ;[1690..1694]:substance:"drug" (SENT (S (SBAR-ADV (IN:[1638..1646] Although) (S (NP-SBJ (PRP:[1647..1649] it)) (VP (VBZ:[1650..1652] is) (ADJP-PRD (JJ:[1653..1657] easy) (S (NP-SBJ (-NONE-:[1657..1657] *)) (VP (TO:[1658..1660] to) (VP (VB:[1661..1670] determine) (NP (ADJP (FW:[1671..1673] in) (FW:[1674..1679] vitro)) (JJ:[1680..1689] metabolic) (NN:[1690..1694] drug) (NNS:[1696..1708] interactions))))))))) (,:[1708..1709] ,) (NP-SBJ (NP (DT:[1710..1713] the) (NML (NML (ADJP-1 (JJ:[1714..1720] proper)) (NN:[1721..1735] interpretation)) (CC:[1736..1739] and) (NML (ADJP-1 (-NONE-:[1739..1739] *P*)) (NN:[1740..1753] extrapolation)))) (PP (IN:[1754..1756] of) (NP (ADJP (FW:[1757..1759] in) (FW:[1760..1765] vitro)) (NN:[1767..1778] interaction) (NNS:[1779..1783] data))) (PP (TO:[1784..1786] to) (NP (ADJP (FW:[1787..1789] in) (FW:[1790..1794] vivo)) (NNS:[1795..1805] situations)))) (VP (VBP:[1806..1813] require) (NP (NP (DT:[1814..1815] a) (JJ:[1816..1820] good) (NN:[1821..1834] understanding)) (PP (IN:[1835..1837] of) (NP (JJ:[1839..1854] pharmacokinetic) (NNS:[1855..1865] principles))))) (.:[1865..1866] .))) ;sentence 15 Span:1867..2111 ;From the viewpoint of drug therapy, to avoid potential drug-drug ;interactions, it is desirable to develop a new drug candidate that is not a ;potent CYP inhibitor or inducer and the metabolism of which is not readily ;inhibited by other drugs. ;[1889..1893]:substance:"drug" ;[1923..1927]:substance:"drug" ;[1928..1932]:substance:"drug" ;[1980..1984]:substance:"drug" ;[2017..2020]:cyp450:"CYP" ;[2021..2030]:substance:"inhibitor" ;[2034..2041]:substance:"inducer" ;[2105..2110]:substance:"drugs" (SENT (S (PP (IN:[1867..1871] From) (NP (NP (DT:[1872..1875] the) (NN:[1876..1885] viewpoint)) (PP (IN:[1886..1888] of) (NP (NN:[1889..1893] drug) (NN:[1894..1901] therapy))))) (,:[1901..1902] ,) (S-PRP (NP-SBJ (-NONE-:[1902..1902] *)) (VP (TO:[1903..1905] to) (VP (VB:[1906..1911] avoid) (NP (JJ:[1913..1922] potential) (NML (NN:[1923..1927] drug) (HYPH:[1927..1928] -) (NN:[1928..1932] drug)) (NNS:[1933..1945] interactions))))) (,:[1945..1946] ,) (NP-SBJ (PRP:[1947..1949] it)) (VP (VBZ:[1950..1952] is) (ADJP-PRD (JJ:[1953..1962] desirable)) (S-ADV (NP-SBJ (-NONE-:[1962..1962] *)) (VP (TO:[1963..1965] to) (VP (VB:[1966..1973] develop) (NP (NP (DT:[1974..1975] a) (JJ:[1976..1979] new) (NN:[1980..1984] drug) (NN:[1986..1995] candidate)) (SBAR (SBAR (WHNP-3 (WDT:[1996..2000] that)) (S (NP-SBJ-3 (-NONE-:[2000..2000] *T*)) (VP (VBZ:[2001..2003] is) (RB:[2004..2007] not) (NP-PRD (DT:[2008..2009] a) (NML (NML (ADJP-1 (JJ:[2010..2016] potent)) (NML-2 (NN:[2017..2020] CYP)) (NN:[2021..2030] inhibitor)) (CC:[2031..2033] or) (NML (ADJP-1 (-NONE-:[2033..2033] *P*)) (NML-2 (-NONE-:[2033..2033] *P*)) (NN:[2034..2041] inducer))))))) (CC:[2042..2045] and) (SBAR (WHNP-4 (NP (DT:[2046..2049] the) (NN:[2050..2060] metabolism)) (WHPP (IN:[2061..2063] of) (WHNP (WDT:[2065..2070] which)))) (S (NP-SBJ-4 (-NONE-:[2070..2070] *T*)) (VP (VBZ:[2071..2073] is) (RB:[2074..2077] not) (ADVP (RB:[2078..2085] readily)) (VP (VBN:[2086..2095] inhibited) (NP-4 (-NONE-:[2095..2095] *)) (PP (IN:[2096..2098] by) (NP-LGS (JJ:[2099..2104] other) (NNS:[2105..2110] drugs))))))))))))) (.:[2110..2111] .))) ;sentence 16 Span:2112..2330 ;In reality, drug interaction by mutual inhibition between drugs is almost ;inevitable, because CYP-mediated metabolism represents a major route of ;elimination of many drugs, which can compete for the same CYP enzyme. ;[2124..2128]:substance:"drug" ;[2171..2176]:substance:"drugs" ;[2207..2210]:cyp450:"CYP" ;[2280..2285]:substance:"drugs" ;[2319..2329]:cyp450:"CYP enzyme" (SENT (S (PP (IN:[2112..2114] In) (NP (NN:[2115..2122] reality))) (,:[2122..2123] ,) (NP-SBJ (NP (NN:[2124..2128] drug) (NN:[2129..2140] interaction)) (PP (IN:[2141..2143] by) (NP (NP (JJ:[2145..2151] mutual) (NN:[2152..2162] inhibition)) (PP (IN:[2163..2170] between) (NP (NNS:[2171..2176] drugs)))))) (VP (VBZ:[2177..2179] is) (ADJP-PRD (RB:[2180..2186] almost) (JJ:[2187..2197] inevitable)) (,:[2197..2198] ,) (SBAR-PRP (IN:[2199..2206] because) (S (NP-SBJ (ADJP (NN:[2207..2210] CYP) (HYPH:[2210..2211] -) (VBN:[2211..2219] mediated)) (NN:[2221..2231] metabolism)) (VP (VBZ:[2232..2242] represents) (NP (NP (DT:[2243..2244] a) (JJ:[2245..2250] major) (NN:[2251..2256] route)) (PP (IN:[2257..2259] of) (NP (NP (NN:[2260..2271] elimination)) (PP (IN:[2272..2274] of) (NP (NP (JJ:[2275..2279] many) (NNS:[2280..2285] drugs)) (,:[2285..2286] ,) (SBAR (WHNP-1 (WDT:[2287..2292] which)) (S (NP-SBJ-1 (-NONE-:[2292..2292] *T*)) (VP (MD:[2293..2296] can) (VP (VB:[2298..2305] compete) (PP (IN:[2306..2309] for) (NP (DT:[2310..2313] the) (JJ:[2314..2318] same) (NN:[2319..2322] CYP) (NN:[2323..2329] enzyme)))))))))))))))) (.:[2329..2330] .))) ;sentence 17 Span:2331..2586 ;The clinical significance of a metabolic drug interaction depends on the ;magnitude of the change in the concentration of active species (parent drug ;and/or active metabolites) at the site of pharmacological action and the ;therapeutic index of the drug. ;[2372..2376]:substance:"drug" ;[2477..2481]:substance:"drug" ;[2496..2507]:substance:"metabolites" ;[2581..2585]:substance:"drug" (SENT (S (NP-SBJ (NP (DT:[2331..2334] The) (JJ:[2335..2343] clinical) (NN:[2344..2356] significance)) (PP (IN:[2357..2359] of) (NP (DT:[2360..2361] a) (JJ:[2362..2371] metabolic) (NN:[2372..2376] drug) (NN:[2378..2389] interaction)))) (VP (VBZ:[2390..2397] depends) (PP-CLR (IN:[2398..2400] on) (NP (NP (NP (DT:[2401..2404] the) (NN:[2405..2414] magnitude)) (PP (IN:[2415..2417] of) (NP (NP (DT:[2418..2421] the) (NN:[2422..2428] change)) (PP (IN:[2429..2431] in) (NP (NP (DT:[2432..2435] the) (NN:[2436..2449] concentration)) (PP (IN:[2450..2452] of) (NP (NP (JJ:[2454..2460] active) (NN:[2461..2468] species)) (PRN (-LRB-:[2469..2470] -LRB-) (NP (NP (NN:[2470..2476] parent) (NN:[2477..2481] drug)) (CC:[2482..2488] and/or) (NP (JJ:[2489..2495] active) (NNS:[2496..2507] metabolites))) (-RRB-:[2507..2508] -RRB-)))) (PP-LOC (IN:[2509..2511] at) (NP (NP (DT:[2512..2515] the) (NN:[2516..2520] site)) (NP (IN:[2521..2523] of) (JJ:[2525..2540] pharmacological) (NN:[2541..2547] action))))))))) (CC:[2548..2551] and) (NP (NP (DT:[2552..2555] the) (JJ:[2556..2567] therapeutic) (NN:[2568..2573] index)) (PP (IN:[2574..2576] of) (NP (DT:[2577..2580] the) (NN:[2581..2585] drug))))))) (.:[2585..2586] .))) ;sentence 18 Span:2587..2750 ;The smaller the difference between toxic and effective concentration, the ;greater the likelihood that a drug interaction will have serious clinical ;consequences. ;[2693..2697]:substance:"drug" (SENT (FRAG (NP (NP (DT:[2587..2590] The) (JJR:[2591..2598] smaller)) (NP (NP (DT:[2599..2602] the) (NN:[2604..2614] difference)) (PP (IN:[2615..2622] between) (NP (NP (JJ:[2623..2628] toxic) (NML-1 (-NONE-:[2628..2628] *P*))) (CC:[2629..2632] and) (NP (JJ:[2633..2642] effective) (NML-1 (NN:[2643..2656] concentration))))))) (,:[2656..2657] ,) (NP (NP (DT:[2658..2661] the) (JJR:[2662..2669] greater)) (NP (NP (DT:[2670..2673] the) (NN:[2674..2684] likelihood)) (SBAR (IN:[2686..2690] that) (S (NP-SBJ (DT:[2691..2692] a) (NN:[2693..2697] drug) (NN:[2698..2709] interaction)) (VP (MD:[2710..2714] will) (VP (VB:[2715..2719] have) (NP (JJ:[2720..2727] serious) (JJ:[2728..2736] clinical) (NNS:[2737..2749] consequences)))))))) (.:[2749..2750] .))) ;sentence 19 Span:2751..2889 ;Thus, careful evaluation of potential drug interactions of a new drug ;candidate during the early stage of drug development is essential. ;[2790..2794]:substance:"drug" ;[2817..2821]:substance:"drug" ;[2859..2863]:substance:"drug" (SENT (S (ADVP (RB:[2751..2755] Thus)) (,:[2755..2756] ,) (NP-SBJ (NP (JJ:[2757..2764] careful) (NN:[2766..2776] evaluation)) (PP (IN:[2777..2779] of) (NP (NP (JJ:[2780..2789] potential) (NN:[2790..2794] drug) (NNS:[2795..2807] interactions)) (PP (IN:[2808..2810] of) (NP (DT:[2811..2812] a) (JJ:[2813..2816] new) (NN:[2817..2821] drug) (NN:[2822..2831] candidate))))) (PP-TMP (IN:[2832..2838] during) (NP (NP (DT:[2839..2842] the) (JJ:[2844..2849] early) (NN:[2850..2855] stage)) (PP (IN:[2856..2858] of) (NP (NN:[2859..2863] drug) (NN:[2864..2875] development)))))) (VP (VBZ:[2876..2878] is) (ADJP-PRD (JJ:[2879..2888] essential))) (.:[2888..2889] .))) ;section 20 Span:2893..2911 ;Publication Types: (SEC (NP (NNP:[2893..2904] Publication) (NNP:[2905..2910] Types) (::[2910..2911] :))) ;section 21 Span:2917..2923 ;Review (SEC (NP (NNP:[2917..2923] Review))) ;section 22 Span:2929..2945 ;Review, Academic (SEC (NP (NNP:[2929..2935] Review) (,:[2935..2936] ,) (NNP:[2937..2945] Academic))) ;section 23 Span:2949..2993 ;PMID: 9839089 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[2949..2953] PMID) (::[2953..2954] :) (CD:[2955..2962] 9839089) (NN:[2963..2964] -LSB-) (NNP:[2964..2970] PubMed) (::[2971..2972] -) (NN:[2973..2980] indexed) (IN:[2981..2984] for) (NNP:[2985..2992] MEDLINE) (-RRB-:[2992..2993] -RSB-)))