Summary: Dibenzoquinolines derived in plants from (S)-reticuline (BENZYLISOQUINOLINES).

Top Publications

  1. Ivorra M, Valiente M, Martinez S, Madrero Y, Noguera M, Cassels B, et al. 8-NH2-boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structural requirements for aporphines at alpha1-adrenoceptor subtypes. Planta Med. 2005;71:897-903 pubmed
    ..37 +/- 0.21) vs. alpha(1B)-AR (pKi = 5.53 +/- 0.11) exhibited by 1,2,9,10-tetraoxygenated aporphines, but shows low affinity for alpha(1D)-AR (pKi < 2.5)...
  2. Huang R, Chen C, Huang Y, Ou J, Hu C, Chen C, et al. Anti-tumor effects of d-dicentrine from the root of Lindera megaphylla. Planta Med. 1998;64:212-5 pubmed
    ..All these data indicated that d-dicentrine has potential anti-tumor applications. ..
  3. Chiao C, Lee S, Wu C, Su M. Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia. Naunyn Schmiedebergs Arch Pharmacol. 2005;371:34-43 pubmed
    ..These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO. and O(2).(-) production. ..
  4. Tang H, Zhao H, Zhong S, Wang Z, Chen Z, Liang H. Novel oxoisoaporphine-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. Bioorg Med Chem Lett. 2012;22:2257-61 pubmed publisher
    ..The result encourages us to study this class of compounds thoroughly and systematically. ..
  5. Konkimalla V, Efferth T. Inhibition of epidermal growth factor receptor over-expressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine. Biochem Pharmacol. 2010;79:1092-9 pubmed publisher
    ..The cell cycle might be arrested by dicentrine-induced DNA lesions. ..
  6. Ma W, Lu Y, Hu R, Chen J, Zhang Z, Pan Y. Application of ionic liquids based microwave-assisted extraction of three alkaloids N-nornuciferine, O-nornuciferine, and nuciferine from lotus leaf. Talanta. 2010;80:1292-7 pubmed publisher
    ..9998 and 0.9999. The recoveries of all methods were in the range of 94.6% and 105.5% with RSD lower than 6.6%, which indicated that the proposed method was credible. ..
  7. Yu S, Kang Y, Chen C, Teng C. Effects of dicentrine on haemodynamic, plasma lipid, lipoprotein level and vascular reactivity in hyperlipidaemic rats. Br J Pharmacol. 1993;108:1055-61 pubmed
    ..Dicentrine may thus hold potential for the reduction of two of the major risk factors, hypertension and hyperlipidaemia, for cardiovascular disease. ..
  8. Sotnikova R, Kettmann V, Kostalova D, Taborska E. Relaxant properties of some aporphine alkaloids from Mahonia aquifolium. Methods Find Exp Clin Pharmacol. 1997;19:589-97 pubmed
  9. Hoet S, Stévigny C, Block S, Opperdoes F, Colson P, Baldeyrou B, et al. Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases. Planta Med. 2004;70:407-13 pubmed
    ..In a previous investigation, we showed that the alkaloid plant extract and the isolated aporphines possessed in vitro cytotoxic properties...

More Information


  1. Hu L, Xu W, Zhang X, Su J, Liu X, Li H, et al. In-vitro and in-vivo evaluations of cytochrome P450 1A2 interactions with nuciferine. J Pharm Pharmacol. 2010;62:658-62 pubmed publisher
    ..The effects of nuciferine, a major active aporphine alkaloid from the leaves of Nelumbo nucifera Gaertn, on a cytochrome P450 1A2 (CYP1A2) probe substrate were investigated in vitro and in vivo...
  2. Chen W, Tzeng H, Ku H, Ho Y, Lee S, Su M. Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-?B signaling. Naunyn Schmiedebergs Arch Pharmacol. 2010;382:441-53 pubmed publisher
  3. Yu S, Hsu S, Ko F, Chen C, Huang Y, Huang T, et al. Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Br J Pharmacol. 1992;106:797-801 pubmed
    ..6. These results suggest that dicentrine may have therapeutic potential as an oral antihypertensive drug via alpha-adrenoceptor blockade. ..
  4. Stévigny C, Bailly C, Quetin Leclercq J. Cytotoxic and antitumor potentialities of aporphinoid alkaloids. Curr Med Chem Anticancer Agents. 2005;5:173-82 pubmed
    ..Simple aporphinoids (boldine, dicentrine) as well as oxo-, pro- and dehydro-aporphines, and dimeric forms such as thalicarpine, are discussed here...
  5. Tang H, Wei Y, Zhang C, Ning F, Qiao W, Huang S, et al. Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase. Eur J Med Chem. 2009;44:2523-32 pubmed publisher
    ..Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme. ..
  6. Tang H, Zhao L, Zhao H, Huang S, Zhong S, Qin J, et al. Hybrids of oxoisoaporphine-tacrine congeners: novel acetylcholinesterase and acetylcholinesterase-induced ?-amyloid aggregation inhibitors. Eur J Med Chem. 2011;46:4970-9 pubmed publisher
  7. Nguyen K, Ta T, Pham T, Nguyen Q, Pham H, Mishra S, et al. Nuciferine stimulates insulin secretion from beta cells-an in vitro comparison with glibenclamide. J Ethnopharmacol. 2012;142:488-95 pubmed publisher
    ..Several Asian plants are known for their anti-diabetic properties and produce alkaloids and flavonoids that may stimulate insulin secretion...
  8. Montrucchio D, Miguel O, Zanin S, da Silva G, Cardozo A, Santos A. Antinociceptive effects of a chloroform extract and the alkaloid dicentrine isolated from fruits of Ocotea puberula. Planta Med. 2012;78:1543-8 pubmed
    ..The mechanism by which CF and the alkaloid produced antinociception still remains unclear, but the adenosinergic or opioid system seems unlikely to be involved in this action...
  9. Chen Z, Liu Y, Peng Y, Hong X, Wang H, Zhang M, et al. Synthesis, characterization, and in vitro antitumor properties of gold(III) compounds with the traditional Chinese medicine (TCM) active ingredient liriodenine. J Biol Inorg Chem. 2012;17:247-61 pubmed publisher
    ..Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species. ..
  10. Prado Prado F, Garcia Mera X, Escobar M, Sobarzo Sanchez E, Yáñez M, Riera Fernandez P, et al. 2D MI-DRAGON: a new predictor for protein-ligands interactions and theoretic-experimental studies of US FDA drug-target network, oxoisoaporphine inhibitors for MAO-A and human parasite proteins. Eur J Med Chem. 2011;46:5838-51 pubmed publisher
    ..The more active compound OXO5 presented IC(50) = 0.00083 ?M, notably better than the control drug Clorgyline. ..
  11. Mollataghi A, Coudiere E, Hadi A, Mukhtar M, Awang K, Litaudon M, et al. Anti-acetylcholinesterase, anti-?-glucosidase, anti-leishmanial and anti-fungal activities of chemical constituents of Beilschmiedia species. Fitoterapia. 2012;83:298-302 pubmed publisher
    ..All of these isolates were evaluated for their anti-acetylcholinesterase (AChE), anti-?-glucosidase, anti-leishmanial and anti-fungal activities. Compounds 1-12 exhibited strong to moderate bioactivities in aforementioned bioassays. ..
  12. da Silva D, Tulli E, Militão G, Costa Lotufo L, Pessoa C, de Moraes M, et al. The antitumoral, trypanocidal and antileishmanial activities of extract and alkaloids isolated from Duguetia furfuracea. Phytomedicine. 2009;16:1059-63 pubmed publisher
    ..01 microM). Duguetine and duguetine beta-N-oxide caused considerable antitumoral activity in every cell lines evaluated, although duguetine was more active against trypomastigote forms (IC(50) 9.32 microM) than other alkaloids tested. ..
  13. Fernandez J, Lagos P, Rivera P, Zamorano Ponce E. Effect of boldo (Peumus boldus Molina) infusion on lipoperoxidation induced by cisplatin in mice liver. Phytother Res. 2009;23:1024-7 pubmed publisher
    ..These findings suggest the potential use of the infusion as a chemoprotector...
  14. Tsai T, Wang G, Lin L. Vasorelaxing alkaloids and flavonoids from Cassytha filiformis. J Nat Prod. 2008;71:289-91 pubmed publisher
    ..50 to 32.81 microM at the test concentrations. ..
  15. Sobarzo Sanchez E, de la Fuente J, Castedo L. Synthesis and total assignment of 1H and 13C NMR spectra of new oxoisoaporphines by long-range heteronuclear correlations. Magn Reson Chem. 2005;43:1080-3 pubmed
    ..The structures were confirmed and 1H and 13C NMR spectra were completely assigned using two-dimensional NMR techniques. ..
  16. Chi T, Lee S, Su M. Antihyperglycemic effect of aporphines and their derivatives in normal and diabetic rats. Planta Med. 2006;72:1175-80 pubmed
    The antihyperglycemic actions of some aporphines and their derivatives in normal Wistar, streptozotocin (STZ)-induced diabetic (IDDM) and nicotinamide-STZ induced diabetic (NIDDM) rats were investigated in this study...
  17. Fan S, Yu D, Gu Y, Zhang M, Zhang L, Li G. [Determination of magnoflorine in Coptidis Rhizoma and Phellodendri Chinensis Cortex by LC-MS]. Zhongguo Zhong Yao Za Zhi. 2010;35:3322-4 pubmed
    ..352-2720 microg x L(-1). The average recovery was above 98%. The method is simple, sensitive and accurate, it can be used for determination of magnoflorine in Rhizoma Coptidis and Cortex Phellodendri Chinensis. ..
  18. Hawkes G, De Wet H, Li J. Polar compounds isolated from the leaves of Albertisia delagoensis (Menispermaceae). Molecules. 2011;16:9153-60 pubmed publisher
    ..Earlier reports of antiplasmodial activity of roemrefidine and of A. delagoensis extracts are correlated with this study and with the antipyretic properties of neutral aqueous extracts...
  19. Feng Y, Yang A, Liu J, Di D, Liu Y, Li M. [Extraction and purification of isocorydine from Dicranostigma leptopodum]. Zhong Yao Cai. 2013;36:807-9 pubmed
    ..LX28 resin exhibited higher adsorption efficiency. Under the above optimum conditions, the extraction yield of isocorydine is 0.88%. The purity of isocorydine can reach 85.34% with a yield rate of 68.64%. ..
  20. Misik V, Bezakova L, Malekova L, Kostalova D. Lipoxygenase inhibition and antioxidant properties of protoberberine and aporphine alkaloids isolated from Mahonia aquifolium. Planta Med. 1995;61:372-3 pubmed
    ..Inhibition of lipoxygenase by these compounds may contribute to the therapeutic effect of M. aquifolium extracts in the treatment of psoriasis. ..
  21. Fu C, Yin W, Zhou Z. [Studies on the aporphine alkaloids from Fissistigma oldhamii (Hemsl.) Merr]. Zhong Yao Cai. 2007;30:409-12 pubmed
    ..Merr. They were identified as romucosine(I), xylopine(II), O-methylmoschatolineIII), oxoxylopine(IV). Compounds I is obtained from this plant for the first time. ..
  22. Lin C, Chang G, Su M, Wu Y, Teng C, Ko F. Pharmacological characteristics of liriodenine, isolated from Fissistigma glaucescens, a novel muscarinic receptor antagonist in guinea-pigs. Br J Pharmacol. 1994;113:275-81 pubmed
    ..It is more potent in smooth muscle than in cardiac preparations. It also acts as a blocker of voltage-dependent Ca2+ channels at a high concentration (300 microM). ..
  23. Hidalgo M, Farah M, Carrasco L, Fernandez E. Photostability and photoprotection factor of boldine and glaucine. J Photochem Photobiol B. 2005;80:65-9 pubmed
    ..The photoprotection capacity was evaluated before and after irradiation. Results indicate that the values before irradiation are similar for all three compounds, only glaucine increasing its capacity with length of irradiation time. ..
  24. Tringali C, Spatafora C, Calì V, Simmonds M. Antifeedant constituents from Fagara macrophylla. Fitoterapia. 2001;72:538-43 pubmed
    ..littoralis. 1-Hydroxy-3-methoxy-N-methyl-acridone (2), arborinine (3), tembetarine (7) and magnoflorine (8) were antifeedant against S. frugiperda. ..
  25. Chiao C, Lee S, Wu C, Su M. N-Allylsecoboldine as a novel agent prevents acute renal failure during endotoxemia. Eur J Pharmacol. 2006;535:291-300 pubmed
    ..However, the role of alpha1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear. ..
  26. Meyer G, Meyer M, Wissenbach D, Maurer H. Studies on the metabolism and toxicological detection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC-MS, LC-MS(n) and LC-high-resolution MS(n). J Mass Spectrom. 2013;48:24-41 pubmed publisher
    ..Both allowed confirming an intake of glaucine in rat urine after a dose of 2 mg/kg body mass corresponding to a common abuser's dose...
  27. Han Q, Jiang B, Mei S, Ding G, Sun H, Xie J, et al. Constituents from the roots of Semiaquilegia adoxoides. Fitoterapia. 2001;72:86-8 pubmed
    ..The isolation of griffonilide (1), lithospermoside (2) and magnoflorine (3) from the roots of Semiaquilegia adoxoides is reported. ..
  28. Legendre O, Pecic S, Chaudhary S, Zimmerman S, Fantegrossi W, Harding W. Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010;20:628-31 pubmed publisher
    ..Nantenine displayed high affinity and selectivity for the alpha(1A) adrenergic receptor among several other receptors suggesting that this alpha(1) subtype may be significantly involved in the anti-MDMA effects of the enantiomers. ..
  29. Ma J, Jones S, Marshall R, Johnson R, Hecht S. A DNA-damaging oxoaporphine alkaloid from Piper caninum. J Nat Prod. 2004;67:1162-4 pubmed
    ..Compound 1 exhibited potent inhibitory activity in a yeast cytotoxicity assay with IC(50) values of 50.2 nM toward RS321NpRAD52 grown on glucose versus 293 nM toward the same yeast strain grown on galactose. ..
  30. Wang X, Dong H, Yang B, Liu D, Duan W, Huang L. Preparative isolation of alkaloids from Dactylicapnos scandens using pH-zone-refining counter-current chromatography by changing the length of the separation column. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879:3767-70 pubmed publisher
    ..0 g of the crude extracts and each with 99.2%, 96.5%, 99.3%, 99.5% purity as determined by HPLC. The chemical structures of these compounds were confirmed by positive ESI-MS and (1)H NMR...
  31. Deng Y, Tang T, Li X, Wu F. A new aporphine alkaloid from Sabia yunnanensis. Nat Prod Res. 2007;21:28-32 pubmed
    ..Their structures were established on the basis of spectral analysis. ..
  32. Indra B, Tadano T, Nakagawasai O, Arai Y, Yasuhara H, Ohizumi Y, et al. Suppressive effect of nantenine, isolated from Nandina domestica Thunberg, on the 5-hydroxy-L-tryptophan plus clorgyline-induced head-twitch response in mice. Life Sci. 2002;70:2647-56 pubmed
    ..1 microM) and D2-dopaminergic (Ki = 1.7 microM) receptors of the mouse brain. These results suggest that nantenine inhibits l-5-HTP plus clorgyline-induced head- twitch response by blocking 5-HT2A receptors in the central nervous system...
  33. Lu Z, Sun W, Duan X, Yang Z, Liu Y, Tu P. [Chemical constituents from Corydalis yanhusuo]. Zhongguo Zhong Yao Za Zhi. 2012;37:235-7 pubmed
    ..Compounds 13, 20, 21, and 22 were isolated from this plant for the first time. ..
  34. Kuo R, Chang F, Chen C, Teng C, Yen H, Wu Y. Antiplatelet activity of N-methoxycarbonyl aporphines from Rollinia mucosa. Phytochemistry. 2001;57:421-5 pubmed
  35. Gunes H, Gözler B. Two novel proaporphine-tryptamine dimers from Roemeria hybrida. Fitoterapia. 2001;72:875-86 pubmed
    ..NMR data allowed a facile assignment of these proaporphine-tryptamine dimers into different stereochemical subgroups. ..
  36. Chaudhary S, Ponnala S, Legendre O, Gonzales J, Navarro H, Harding W. New aporphinoid 5-HT2A and ?1A antagonists via structural manipulations of nantenine. Bioorg Med Chem. 2011;19:5861-8 pubmed publisher
    ..The C2 alkyloxy analogs studied were generally selective for ?(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT(2A) antagonists known presently. ..
  37. Loghin F, Chagraoui A, Asencio M, Comoy E, Speisky H, Cassels B, et al. Effects of some antioxidative aporphine derivatives on striatal dopaminergic transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice. Eur J Pharm Sci. 2003;18:133-40 pubmed
    ..These data suggest that potent in vitro antioxidative properties and the ability to cross the blood-brain barrier are not sufficient criteria to predict the inhibition of neuronal degeneration induced by MPTP. ..
  38. Ma Y, Shang Q, Bai Y, Meng X, Kang S. [Study on pharmacokinetics of crebanine injection in rabbits]. Zhongguo Zhong Yao Za Zhi. 2007;32:630-2 pubmed
    ..To develop an HPLC method for the determination of serum level of Crebanine (Cre) and study on the pharmacokinetics of Cre injection in rabbits...
  39. Chang W, Lee S, Su M. Attenuation of post-ischemia reperfusion injury by thaliporphine and morphine in rat hearts. J Biomed Sci. 2005;12:611-9 pubmed
  40. Chang W, Chung C, Wu Y, Su M. The vascular and cardioprotective effects of liriodenine in ischemia-reperfusion injury via NO-dependent pathway. Nitric Oxide. 2004;11:307-15 pubmed
    ..These results demonstrate that liriodenine reduces the extent of cardiovascular injuries under ischemia-reperfusion conditions mainly by preserving the eNOS and the NO production. ..
  41. Wu W, Moyer M. Electrospray tandem mass spectrometry for structural characterization of aporphine- benzylisoquinoline alkaloids. Eur J Mass Spectrom (Chichester). 2004;10:683-9 pubmed
    ..More than 10 microg quantities of each investigated alkaloid or other isoquinoline and aporphine analogs needed for the CI-MS, EI-MS and FAB-MS analysis from the previous studies...
  42. Keating C, Orchard I. The effects of dopamine agonists and antagonists on the secretory responses in the salivary glands of the locust (Locusta migratoria). J Insect Physiol. 2004;50:17-23 pubmed
    ..The cAMP analogue 8-Bromo cAMP also increased secretion rates from isolated salivary glands. These data and the rank order of potency of the agonists and antagonists in this screen suggest that this receptor is a D1-type receptor. ..
  43. Huang J, Guo J, Duan G. [Determination of 7 bio-active alkaloids in Stephania plants by RP-HPLC]. Yao Xue Xue Bao. 1998;33:528-33 pubmed
    ..Based on the results, some species with high content of the 7 bio-active alkaloids were selected. The study provided some useful information for the utilization of medicinal plant resources in the genus Stephania...
  44. Coy Barrera E, Cuca Suarez L. In vitro inhibitory activities of Lauraceae aporphine alkaloids. Nat Prod Commun. 2010;5:383-6 pubmed
    ..9-116 microM range) and PAF- and AA-induced platelet aggregation, while only four and three of them were good COX-1 and 5-LOX inhibitors, respectively. (+)-N-acetyl-nornantenine 6 was the most potent COX-2, 5-LOX, AA and PAF inhibitor...
  45. Wu W, McKown L. The in vitro metabolism of thalicarpine, an aporphine-benzyltetrahydroisoquinoline alkaloid, in the rat. API-MS/MS identification of thalicarpine and metabolites. J Pharm Biomed Anal. 2002;30:141-50 pubmed
    ..Pathway 3 formed a major (M6, 28%) and three minor (M5, M7 and M8, each 2-3%) benzylic-cleavage metabolites. Thalicarpine is substantially metabolized by this rat hepatic system. ..
  46. de Lira G, de Andrade L, Florêncio K, da Silva M, Barbosa Filho J, Leitão da Cunha E. Roraimine: a bisbenzylisoquinoline alkaloid from Cissampelos sympodialis roots. Fitoterapia. 2002;73:356-8 pubmed
    ..The roots of Cissampelos sympodialis yielded Roraimine (1), a novel bisbenzylisoquinoline alkaloid and liriodenine (2), a known oxoaporphine alkaloid...
  47. Minami H, Kim J, Ikezawa N, Takemura T, Katayama T, Kumagai H, et al. Microbial production of plant benzylisoquinoline alkaloids. Proc Natl Acad Sci U S A. 2008;105:7393-8 pubmed publisher
  48. Ge Y, Zhu S, Shang M, Zang X, Wang X, Bai Y, et al. Aristololactams and aporphines from the stems of Fissistigma oldhamii (Annonaceae). Phytochemistry. 2013;86:201-7 pubmed publisher
    Two aristololactams, aristololactam GI (1) and aristololactam GII (2), and three aporphines, fissistigamide A (3), fissistigamide B (4) and fissistigmine (5), together with nineteen known alkaloids, one flavone and one anthraquinone were ..
  49. Orallo F. Pharmacological effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in several rat isolated tissues. Planta Med. 2003;69:135-42 pubmed
  50. Yodkeeree S, Wongsirisin P, Pompimon W, Limtrakul P. Anti-invasion effect of crebanine and O-methylbulbocapnine from Stephania venosa via down-regulated matrix metalloproteinases and urokinase plasminogen activator. Chem Pharm Bull (Tokyo). 2013;61:1156-65 pubmed
    ..These findings demonstrated that CN and OMBC mediated HT1080 cell invasion by the reduction of MMP-2, MMP-9, uPA and MT1-MMP expression, possibly by targeting of NF-?B signaling pathway in the HT1080 cells. ..
  51. Lu Z, Zhang Q, Chen R, Yu D. [Study on chemical constituents from branches and leaves of Polyalthia nemoralis]. Zhongguo Zhong Yao Za Zhi. 2011;36:1024-7 pubmed
    ..All the compounds were isolated from the genus Polyalthia for the first time; compounds 6 and 13 showed inhibitation activities against multi tumor cell lines. ..
  52. Mu Q, Tang W, Liu R, Li C, Lou L, Sun H, et al. Constituents from the stems of Goniothalamus griffithii. Planta Med. 2003;69:826-30 pubmed
    ..Among them, the griffinin (2) was isolated as the enol form in two tautomers, and the two known styryllactones, goniothalamin (3) and 8- O-acetylgoniotriol (4), showed selective in vitro antitumor activities. ..
  53. Salminen K, Meyer A, Imming P, Raunio H. CYP2C19 progress curve analysis and mechanism-based inactivation by three methylenedioxyphenyl compounds. Drug Metab Dispos. 2011;39:2283-9 pubmed publisher
    ..The alkaloids bulbocapnine, canadine, and protopine, present in herbal medicines, are new mechanism-based inactivators and the first MDP compounds exhibiting quasi-irreversible inactivation of CYP2C19. ..