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Drug-Target Interaction

Drug

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PubChem ID:202225
Structure:
Synonyms:
2751-09-9
AB00513798
AC1L483V
BPBio1_000145
BSPBio_000131
C12753
CHEMBL564085
D01322
DB01361
Evramicina
FT-0082364
HMS2089B10
HMS2095G13
LMPK04000042
Matromicina
NCGC00179654-01
Oleandocetine
Oleandomycin triacetate
Oleandomycin triacetyl ester
Oleandomycin, triacetate (ester)
Prestwick3_000036
Tao
Tao (TN)
Treolmicina
Triacetyloleandomycin
Triacetyloleandomycin (JAN)
Tribiocillina
Troleandomycin
Troleandomycin (USP/INN)
[(3R,5S,6S,7R,8S,9R,12R,13S,14S,15R)-6-[(2S,3R,4S,6R)-3-acetyloxy-4-(dimet
[(3R,5S,6S,7R,8S,9R,12R,13S,14S,15R)-6-[(2S,3R,4S,6R)-3-acetyloxy-4-dimethylamino-6-methyloxan-2-yl]oxy-8-[(2R,4S,5S,6S)-5-acetyloxy-4-methoxy-6-methyloxan-2-yl]oxy-5,7,9,12,13,15-hexamethyl-10,16-dioxo-1,11-dioxaspiro[2.13]hexadecan-14-yl] acetate
ATC-Codes:

Target

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Uniprot ID:CP2C8_HUMAN
Synonyms:
CYPIIC8
Cytochrome P450 2C8
P450 form 1
P450 IIC2
P450 MP-12/MP-20
S-mephenytoin 4-hydroxylase
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:1PQ2 2NNH 2NNI 2NNJ 2VN0
Structure:
2VN0

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----
----
----
----

References:

12426516
Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin.. Mary F Paine; David A Wagner; Keith A Hoffmaster; Paul B Watkins (2002) Clinical pharmacology and therapeutics display abstract
BACKGROUND: The intravenous (14)C-erythromycin breath test (ERMBT(IV)) does not measure aggregate liver and intestinal cytochrome P450 (CYP) 3A4 activity. Accordingly, we evaluated an oral stable-labeled ((13)C) formulation of the test (ERMBT(oral)) as an alternative CYP3A4 phenotyping probe. METHODS: After an overnight fast, 14 young healthy volunteers (5 women and 9 men) received the ERMBT(IV) (0.07 micromol, 3 muCi), followed by the ERMBT(oral) (500 mg). The next morning, the CYP3A4 inhibitor troleandomycin (500 mg) was given, and both ERMBTs were repeated. After at least 24 hours, the CYP3A4 and P-glycoprotein inducer rifampin (600 mg; INN, rifampicin) was given daily for 7 days, and both ERMBTs were repeated 24 hours after the last dose of rifampin. Plasma samples were collected for 10 hours with each administration of the ERMBT(oral), and erythromycin levels were measured by liquid chromatography-mass spectrometry. Finally, the effect of troleandomycin on erythromycin transport was examined in Caco-2 cell monolayers. RESULTS: Compared with baseline values, the median ERMBT(IV) and ERMBT(oral) results and erythromycin apparent oral clearance (CL/F) all significantly decreased, by at least 70%, with troleandomycin treatment (P =.001 for each comparison). With rifampin treatment, the median ERMBT(IV) result and CL/F increased 2-fold (P < or =.01), but the median ERMBT(oral) result was unchanged (P =.30). There were no rank-order correlations between the ERMBT(IV) and ERMBT(oral) results or between either ERMBT result and CL/F within each treatment group (P > or =.07). In addition, troleandomycin had no effect on erythromycin transport in Caco-2 cells (P > or =.20). CONCLUSIONS: The ERMBT(oral) was influenced by processes in addition to intestinal and hepatic CYP3A4 activity and therefore did not provide a straightforward measure of aggregate CYP3A4 phenotype. The erythromycin-rifampin interaction cannot be attributed to CYP3A4 induction alone and probably also reflected intestinal P-glycoprotein induction.
15054565
3259858
Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme.. D J Waxman; C Attisano; F P Guengerich; D P Lapenson (1988) Archives of biochemistry and biophysics display abstract
Cytochrome P-450-dependent steroid hormone metabolism was studied in isolated human liver microsomal fractions. 6 beta hydroxylation was shown to be the major route of NADPH-dependent oxidative metabolism (greater than or equal to 75% of total hydroxylated metabolites) with each of three steroid substrates, testosterone, androstenedione, and progesterone. With testosterone, 2 beta and 15 beta hydroxylation also occurred, proceeding at approximately 10% and 3-4% the rate of microsomal 6 beta hydroxylation, respectively, in each of the liver samples examined. Rates for the three steroid 6 beta-hydroxylase activities were highly correlated with each other (r = 0.95-0.97 for 25 individual microsomal preparations), suggesting that a single human liver P-450 enzyme is the principal microsomal 6 beta-hydroxylase catalyst with all three steroid substrates. Steroid 6 beta-hydroxylase rates correlated well with the specific content of human P-450NF (r = 0.69-0.83) and with its associated nifedipine oxidase activity (r = 0.80), but not with the rates for debrisoquine 4-hydroxylase, phenacetin O-deethylase, or S-mephenytoin 4-hydroxylase activities or the specific contents of their respective associated P-450 forms in these same liver microsomes (r less than 0.2). These correlative observations were supported by the selective inhibition of human liver microsomal 6 beta hydroxylation by antibody raised to either human P-450NF or a rat homolog, P-450 PB-2a. Anti-P-450NF also inhibited human microsomal testosterone 2 beta and 15 beta hydroxylation in parallel to the 6 beta-hydroxylation reaction. This antibody also inhibited rat P-450 2a-dependent steroid hormone 6 beta hydroxylation in uninduced adult male rat liver microsomes but not the steroid 2 alpha, 16 alpha, or 7 alpha hydroxylation reactions catalyzed by other rat P-450 forms. Finally, steroid 6 beta hydroxylation catalyzed by either human or rat liver microsomes was selectively inhibited by NADPH-dependent complexation of the macrolide antibiotic triacetyloleandomycin, a reaction that is characteristic of members of the P-450NF gene subfamily (P-450 IIIA subfamily). These observations establish that P-450NF or a closely related enzyme is the major catalyst of steroid hormone 6 beta hydroxylation in human liver microsomes, and furthermore suggest that steroid 6 beta hydroxylation may provide a useful, noninvasive monitor for the monooxygenase activity of this hepatic P-450 form.
9321513
Cytochrome P4503A4-mediated N-demethylation of the antiprogestins lilopristone and onapristone.. G R Jang; L Z Benet (1997) Drug metabolism and disposition: the biological fate of chemicals display abstract
The metabolism of two newer antiprogestational agents, lilopristone and onapristone, was investigated using human liver microsomes, and evidence was obtained supporting a principal role of cytochrome P450 (CYP) 3A4 in their N-demethylations. Kinetic studies with microsomes from three organ donors indicated lack of biphasic kinetics at substrate concentrations up to 200 microM, consistent with a single enzyme mediating the oxidations. Selective chemical inhibitors of CYP1A2 (furafylline), CYP2C9 (sulfaphenazole), CYP2D6 (quinidine), and CYP2A6/2E1 (diethyldithiocarbamic acid) did not affect initial rates of metabolism of either steroid. Gestodene and triacetyloleandomycin (selective for CYP3A enzymes) inhibited the demethylations of both antiprogestins by up to 77%. Rabbit polyclonal antibodies to CYP3A4 decreased initial rates of N-demethylation of the antihormones by up to 82%, whereas antibodies to CYP2C9 were not inhibitory. Collectively, these data thus suggest potential drug-drug interactions of these promising new therapeutic agents with concomitantly administered CYP3A4 substrates.
9806945
Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6beta-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin.. H Yamazaki; T Shimada (1998) Drug metabolism and disposition: the biological fate of chemicals display abstract
Roxithromycin has been shown to be a relatively weak inhibitor of cytochrome P450 (P450 or CYP)-dependent drug oxidations, compared with troleandomycin. The potential for roxithromycin and its major metabolites found in human urine [namely the decladinosyl derivative (M1), O-dealkyl derivative (M2), and N-demethyl derivative (M3)] to inhibit testosterone 6beta-hydroxylation after metabolic activation by CYP3A4 was examined and compared with inhibition by troleandomycin and erythromycin in vitro. Of roxithromycin and its studied metabolites, M3 was the most potent in inhibiting CYP3A4-dependent testosterone 6beta-hydroxylation by human liver microsomes and was activated to the inhibitory P450.Fe2+-metabolite complex to the greatest extent. Roxithromycin and its metabolites were N-demethylated by human liver microsomes, although the rates were slower than those measured with troleandomycin and erythromycin as substrates. Recombinant human CYP3A4 in a baculovirus system coexpressing NADPH-P450 reductase was very active in catalyzing the N-demethylation of roxithromycin, M1, and M2, as well as troleandomycin, erythromycin, and M3. The order for inhibition of CYP3A4-dependent testosterone 6beta-hydroxylation activities by these macrolide antibiotics in the recombinant CYP3A4 system was estimated to be troleandomycin > erythromycin >/= M3 >/= M2 > M1 >/= roxithromycin. Erythromycin, roxithromycin, and its metabolites all failed to inhibit CYP1A2-dependent (R)-warfarin 7-hydroxylation and CYP2C9-dependent (S)-warfarin 7-hydroxylation but did inhibit CYP3A4-dependent (R)-warfarin 7-hydroxylation. These results suggest that roxithromycin itself is not as potent an inhibitor of CYP3A4 activities as are troleandomycin and erythromycin, probably because of the slower metabolism of this compound to metabolites M1, M2, and M3 in humans.