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Article: The leucine-rich repeat superfamily of synaptic adhesion molecules: LRRTMs and Slitrks

Ko, J.W., Yonsei University, Seoul, Republic of Korea

Molecules and Cells

(Oct 2012) Volume v. 34, Issue (4), Page(s) p. 335–340

Abstract: Synapses are asymmetric intercellular junctions connected by multiple synaptic cell adhesion molecules (CAMs). Synaptic CAMs function in various stages of synaptogenesis - the process of synapse creation - encompassing synapse formation, maturation, ... ...

Abstract	Synapses are asymmetric intercellular junctions connected by multiple synaptic cell adhesion molecules (CAMs). Synaptic CAMs function in various stages of synaptogenesis - the process of synapse creation - encompassing synapse formation, maturation, refinement, plasticity, and elimination. The list of synaptic CAMs has rapidly grown, although their precise functions of most CAMs at synapses remain incomplete. Members of an emerging class of transmembrane proteins containing leucine-rich repeat (LRR) domains have received considerable recent research attention. In this minireview, I discuss recent findings on LRR-containing synaptic CAMs that impact synapse development and circuit formation, focusing on two families of LRR synaptic CAMs: leucine-rich transmembrane proteins (LRRTMs) and Slit and Trk-like family (Slitrks). Their basic biochemical properties, proposed functions at synapses, physiological significances, and open questions are summarized.
Keywords	PROTEINS ; PROTEINE ; PROTEINAS
Language	English
Document type	Article
ISSN	1016-8478
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article ; Online: Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

Jung, J A / Kim, N / Yang, J-S / Kim, T-e / Kim, J-R / Song, G-S / Kim, H / Ko, J W / Huh, W

Drug research

2014 Volume 64, Issue 12, Page(s) 651–655

Abstract: Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for ... ...

Abstract	Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.
MeSH term(s)	Adult ; Area Under Curve ; Benzamides/administration & dosage ; Benzamides/pharmacokinetics ; Chemistry, Pharmaceutical/methods ; Cross-Over Studies ; Humans ; Imatinib Mesylate ; Male ; Piperazines/administration & dosage ; Piperazines/pharmacokinetics ; Pyrimidines/administration & dosage ; Pyrimidines/pharmacokinetics ; Republic of Korea ; Tablets/administration & dosage ; Tablets/pharmacokinetics ; Therapeutic Equivalency ; Volunteers
Chemical Substances	Benzamides ; Piperazines ; Pyrimidines ; Tablets ; Imatinib Mesylate (8A1O1M485B)
Language	English
Publishing date	2014-12
Publishing country	Germany
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2703847-6
ISSN	2194-9387 ; 2194-9379
ISSN (online)	2194-9387
ISSN	2194-9379
DOI	10.1055/s-0034-1367059
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Article ; Online: Pharmacokinetics of a new once-daily controlled-release sarpogrelate hydrochloride compared with immediate-release formulation and the effect of food.

Kim, T-E / Kim, J-R / Jung, J A / Kim, M-J / Lee, S-Y / Ko, J-W / Jung, W-T / Choi, Y-W / Lee, H J / Kim, S-H / Huh, W

Journal of clinical pharmacy and therapeutics

2014 Volume 39, Issue 2, Page(s) 192–195

Abstract: What is known and objective: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled- ... ...

Abstract	What is known and objective: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. Methods: A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. Results and discussion: After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). What is new and conclusion: After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.
MeSH term(s)	Adult ; Area Under Curve ; Biological Availability ; Chromatography, Liquid ; Cross-Over Studies ; Delayed-Action Preparations ; Drug Administration Schedule ; Food-Drug Interactions ; Half-Life ; Humans ; Male ; Middle Aged ; Models, Biological ; Platelet Aggregation Inhibitors/administration & dosage ; Platelet Aggregation Inhibitors/pharmacokinetics ; Succinates/administration & dosage ; Succinates/pharmacokinetics ; Tandem Mass Spectrometry ; Young Adult
Chemical Substances	Delayed-Action Preparations ; Platelet Aggregation Inhibitors ; Succinates ; sarpogrelate (19P708E787)
Language	English
Publishing date	2014-04
Publishing country	England
Document type	Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	639006-7
ISSN	1365-2710 ; 0269-4727
ISSN (online)	1365-2710
ISSN	0269-4727
DOI	10.1111/jcpt.12117
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Article: Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6.

Ko, J W / Desta, Z / Flockhart, D A

Drug metabolism and disposition: the biological fate of chemicals

1998 Volume 26, Issue 8, Page(s) 775–778

Abstract: We tested the ability of human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP or P450) isoforms to catalyze the N-demethylation of nirvanol-free (S)-mephenytoin [(S)-MP] in vitro. In mixed HLMs, the kinetics of (S)-MP N-demethylation ... ...

Abstract	We tested the ability of human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP or P450) isoforms to catalyze the N-demethylation of nirvanol-free (S)-mephenytoin [(S)-MP] in vitro. In mixed HLMs, the kinetics of (S)-MP N-demethylation suggested two contributing activities. A high-affinity/low-capacity component exhibited a KM of 174.1 microM and a Vmax of 170.5 pmol/mg protein/min, whereas a low-affinity/high-capacity component exhibited a KM of 1911 microM and a Vmax of 3984 pmol/mg protein/min. The activity of the high-affinity component was completely abolished by sulfaphenazole, with little effect on the low-affinity component. Of the recombinant P450 isoforms tested, only CYP2B6 and CYP2C9 formed nirvanol from (S)-MP. The KM value (150 +/- 42 microM) derived for recombinant CYP2C9 was close to that obtained for the high-affinity/low-capacity component in mixed HLMs (KM = 174.1 microM). The predicted contribution of this activity at concentrations (1-25 microM) achieved after a single 100-mg dose of racemic MP is approximately 30% of the rate of nirvanol formation. At concentrations of >1000 microM, we estimate that >90% of the rate can be explained by the low-affinity activity (CYP2B6). Therefore, the N-demethylation of (S)-MP to nirvanol may be a useful means of probing the activity of CYP2B6 in vitro when concentrations of >1000 microM are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of >1000 microM are rarely encountered.
MeSH term(s)	Anticonvulsants/metabolism ; Anticonvulsants/pharmacokinetics ; Aryl Hydrocarbon Hydroxylases ; Cytochrome P-450 CYP2B6 ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 Enzyme System/metabolism ; Humans ; Isoenzymes/metabolism ; Kinetics ; Mephenytoin/analogs & derivatives ; Mephenytoin/metabolism ; Mephenytoin/pharmacokinetics ; Methylation ; Microsomes, Liver/metabolism ; Oxidoreductases, N-Demethylating/metabolism ; Phenotype ; Stereoisomerism ; Steroid 16-alpha-Hydroxylase ; Steroid Hydroxylases/metabolism ; Substrate Specificity
Chemical Substances	Anticonvulsants ; Isoenzymes ; ethylphenylhydantoin (23SM1FA1AK) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Steroid Hydroxylases (EC 1.14.-) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2B6 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2B6 (EC 1.14.14.1) ; Steroid 16-alpha-Hydroxylase (EC 1.14.14.1) ; Oxidoreductases, N-Demethylating (EC 1.5.-) ; Mephenytoin (R420KW629U)
Language	English
Publishing date	1998-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
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Article: Congenital multiple plaque-like glomangiomyoma.

Yang, J S / Ko, J W / Suh, K S / Kim, S T

The American Journal of dermatopathology

1999 Volume 21, Issue 5, Page(s) 454–457

Abstract: Congenital glomus tumor is a rare clinical variant of glomus tumor, and glomangiomyoma is the least frequent histologic type of glomus tumor. We report a case of congenital multiple plaque-like glomangiomyoma in a 38-year-old man with multiple nodules ... ...

Abstract	Congenital glomus tumor is a rare clinical variant of glomus tumor, and glomangiomyoma is the least frequent histologic type of glomus tumor. We report a case of congenital multiple plaque-like glomangiomyoma in a 38-year-old man with multiple nodules and plaques on his left arm and forearm. Histopathologic study showed an angiomatous, nonencapsulated tumor with numerous highly folded dilated vascular lumina scattered throughout the dermis. The lumina were lined by a single layer of flat endothelial cells, and one to several rows of glomus cells were observed adjacent to the endothelial cells. Around large vessels, there was a gradual transition from glomus cells to elongated mature smooth muscle cells with thin and long "blunt-ended" nuclei. Immunohistochemically, there were strong positive reactions for cytoplasmic alpha-smooth muscle actin in glomus cells and smooth muscle cells, vimentin in glomus cells and endothelial cells, and desmin in the smooth muscle cells only. To our knowledge, this is the first case report of congenital multiple plaque-like glomus tumor with the microscopic appearance of a glomangiomyoma.
MeSH term(s)	Actins/analysis ; Adult ; Arm ; Desmin/analysis ; Glomus Tumor/congenital ; Glomus Tumor/metabolism ; Glomus Tumor/pathology ; Humans ; Immunohistochemistry ; Male ; Muscles/metabolism ; Skin/chemistry ; Skin/pathology ; Skin Neoplasms/congenital ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Vimentin/analysis
Chemical Substances	Actins ; Desmin ; Vimentin
Language	English
Publishing date	1999-10
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	448469-1
ISSN	1533-0311 ; 0193-1091
ISSN (online)	1533-0311
ISSN	0193-1091
DOI	10.1097/00000372-199910000-00009
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Article: Pityriasis lichenoides-like mycosis fungoides in children.

Ko, J W / Seong, J Y / Suh, K S / Kim, S T

The British journal of dermatology

1999 Volume 142, Issue 2, Page(s) 347–352

Abstract: We report three children with clinical features of pityriasis lichenoides (scaly red to brown papules and macules) in whom there were histopathological findings of mycosis fungoides (disproportionate epidermotropism, Pautrier's microabscesses, and wiry ... ...

Abstract	We report three children with clinical features of pityriasis lichenoides (scaly red to brown papules and macules) in whom there were histopathological findings of mycosis fungoides (disproportionate epidermotropism, Pautrier's microabscesses, and wiry and coarse collagen bundles). Immunohistochemical staining revealed a prevalence of T lymphocytes in the infiltrate. T-cell receptor gene rearrangement analysis in lesional skin demonstrated rearrangement of the gamma chain in all cases. Human T-cell lymphotropic virus type 1 serology was negative in the two patients in whom this test was performed. Thus, lesions resembling pityriasis lichenoides can be an unusual and potentially misleading presentation of mycosis fungoides.
MeSH term(s)	Child ; Child, Preschool ; Diagnosis, Differential ; Humans ; Male ; Mycosis Fungoides/diagnosis ; Mycosis Fungoides/pathology ; Pityriasis Lichenoides/diagnosis ; Skin Neoplasms/diagnosis ; Skin Neoplasms/pathology
Language	English
Publishing date	1999-08-11
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	80076-4
ISSN	1365-2133 ; 0007-0963
ISSN (online)	1365-2133
ISSN	0007-0963
DOI	10.1046/j.1365-2133.2000.03307.x
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Article: Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19.

Donahue, S R / Flockhart, D A / Abernethy, D R / Ko, J W

Clinical pharmacology and therapeutics

1997 Volume 62, Issue 5, Page(s) 572–577

Abstract: A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and ...

Abstract	A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.
MeSH term(s)	Adult ; Anticonvulsants/blood ; Anticonvulsants/pharmacokinetics ; Aryl Hydrocarbon Hydroxylases ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 Enzyme Inhibitors ; Humans ; Male ; Mixed Function Oxygenases/antagonists & inhibitors ; Phenytoin/blood ; Phenytoin/pharmacokinetics ; Platelet Aggregation Inhibitors/pharmacology ; Ticlopidine/pharmacology
Chemical Substances	Anticonvulsants ; Cytochrome P-450 Enzyme Inhibitors ; Platelet Aggregation Inhibitors ; Phenytoin (6158TKW0C5) ; Mixed Function Oxygenases (EC 1.-) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; Ticlopidine (OM90ZUW7M1)
Language	English
Publishing date	1997-11
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1016/S0009-9236(97)90054-0
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Article: Bioequivalence Study of Two Imatinib Formulations after Single-dose Administration in Healthy Korean Male Volunteers

Jung, J. A. / Kim, N. / Yang, J.-S. / Kim, T.-e. / Kim, J.-R. / Song, G.-S. / Kim, H. / Ko, J. W. / Huh, W.

Drug Research

2014 Volume 64, Issue 12, Page(s) 651–655

Abstract	Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea. An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods. A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The C max value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUC last of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for C max and AUC last were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively. A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.
Keywords	bioequivalence ; imatinib ; Korean ; pharmacokinetics
Language	English
Publishing date	2014-02-18
Publisher	© Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2703847-6
ISSN	2194-9387 ; 2194-9379
ISSN (online)	2194-9387
ISSN	2194-9379
DOI	10.1055/s-0034-1367059
Database	Thieme publisher's database

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Article ; Online: Selective transport of cesium ion in polymeric CTA membrane containing calixcrown ethers.

Kim, J S / Kim, S K / Ko, J W / Kim, E T / Yu, S H / Cho, M H / Kwon, S G / Lee, E H

Talanta

2006 Volume 52, Issue 6, Page(s) 1143–1148

Abstract: A series of calixcrown ethers for which the cavity size of the crown ring is varied from crown-6 to crown-7 to crown-8 were examined for the transport abilities toward alkali metal ions. These ligands were incorporated into supported liquid membranes ( ... ...

Abstract	A series of calixcrown ethers for which the cavity size of the crown ring is varied from crown-6 to crown-7 to crown-8 were examined for the transport abilities toward alkali metal ions. These ligands were incorporated into supported liquid membranes (SLMs) and into polymer inclusion membranes (PIMs) composed of cellulose triacetate (CTA) as a support and 2-nitrophenyl octyl ether (NPOE) and tris(2-butoxyethyl) phosphate (TBEP) as a plasticizer. In both membrane systems, calixcrown-6 showed the best selectivity toward a cesium ion over other alkali metal ions. The polymeric CTA membrane showed more rapid transport rate as well as higher durability than did the SLMs.
Language	English
Publishing date	2006-01-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1500969-5
ISSN	1873-3573 ; 0039-9140
ISSN (online)	1873-3573
ISSN	0039-9140
DOI	10.1016/s0039-9140(00)00489-6
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Article: In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6.

Ko, J W / Desta, Z / Soukhova, N V / Tracy, T / Flockhart, D A

British journal of clinical pharmacology

2000 Volume 49, Issue 4, Page(s) 343–351

Abstract: Aims: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s.: Methods: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and ...

Abstract	Aims: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. Methods: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. Results: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. Conclusions: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.
MeSH term(s)	Anticonvulsants/metabolism ; Antitussive Agents/metabolism ; Aryl Hydrocarbon Hydroxylases ; Chlorzoxazone/metabolism ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 CYP2D6 Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Dextromethorphan/metabolism ; Humans ; Hypoglycemic Agents/metabolism ; In Vitro Techniques ; Kinetics ; Mephenytoin/metabolism ; Microsomes, Liver/drug effects ; Microsomes, Liver/enzymology ; Mixed Function Oxygenases/antagonists & inhibitors ; Muscle Relaxants, Central/metabolism ; Phenacetin/metabolism ; Platelet Aggregation Inhibitors/pharmacology ; Recombinant Proteins ; Ticlopidine/pharmacology ; Tolbutamide/metabolism
Chemical Substances	Anticonvulsants ; Antitussive Agents ; Cytochrome P-450 CYP2D6 Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Hypoglycemic Agents ; Muscle Relaxants, Central ; Platelet Aggregation Inhibitors ; Recombinant Proteins ; Dextromethorphan (7355X3ROTS) ; Tolbutamide (982XCM1FOI) ; Mixed Function Oxygenases (EC 1.-) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; Phenacetin (ER0CTH01H9) ; Chlorzoxazone (H0DE420U8G) ; Ticlopidine (OM90ZUW7M1) ; Mephenytoin (R420KW629U)
Language	English
Publishing date	2000-04
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1046/j.1365-2125.2000.00175.x
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