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Drug-Target Interaction

Drug

show drug details
PubChem ID:3690
Structure:
Synonyms:
(+)-ifosfamid
(+)-ifosphamide
(+)-tetrahydro-n,3-bis(2-chloroethyl)-2h-1,3,2-oxazaphosphorin-2-amine 2-oxide
(+-)-Ifosfamid
(+-)-Ifosphamide
(+-)-Tetrahydro-N,3-bis(2-chloroethyl)-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide
(D,L)-Ifosfamide
(R,S)-Ifosphamide
(R,S)-N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide
1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-, 2-oxide
1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-, 2-oxide
2,3-(N,N(sup 1)-Bis(2-chloroethyl)diamido)-1,3,2-oxazaphosphoridinoxyd
2,3-N,N(sup 1)-Bis(2-chloroethyl)diamido-1,3,2-oxazaphosphoridinoxy-
2,3-N,N(sup 1)-Bis(2-chloroethyl)diamido-1,3,2-oxazaphosphoridinoxyd
2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis( 2-chloroethyl)tetrahydro-, 2-oxide
2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-,
2H-1,3,2-Oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-, 2-oxide
2h-1,3,2-oxazaphosphorin-2-amine, tetrahydro-n,3-bis(2-chloroethyl)-, 2-oxide, (+)-
2H-1,3,2-Oxazaphosphorin-2-amine, tetrahydro-N,3-bis(2-chloroethyl)-, 2-oxide, (+-)-
2H-1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-, 2-oxide
2H-1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-, 2-oxide (8CI)
2H-1,3,2-Oxazaphosphorine, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-, 2-oxide
3-(2-Chloroethyl)-2-((2-chloroethyl)amino)perhydro-2H-1,3,2-oxazaphosphorine oxide
3-(2-Chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]perhydro-2H-1,3,2-oxazaphosphorine oxide
3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]perhydro-2H-1,3,2-oxazaphosphorineoxide
3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2- oxide
3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
36341-88-5
3778-73-2
84711-20-6
A 4942
AB00513932
AIDS-126436
AIDS126436
ASTA Z 4942
BPBio1_000865
BRN 0611835
BSPBio_000785
C07047
C7H15Cl2N2O2P
CAS-3778-73-2
CCRIS 352
Cyfos
D00343
D007069
DB01181
DRG-0207
EINECS 223-237-3
Holoxan
Holoxan 1000
HSDB 7023
I-Phosphamide
Ifex
Ifex (TN)
IFEX/MESNEX KIT
Ifosamide
Ifosfamid
Ifosfamida
Ifosfamida [INN-Spanish]
Ifosfamide
Ifosfamide (JAN/USP/INN)
Ifosfamide Sterile
Ifosfamide [USAN:BAN:INN:JAN]
Ifosfamide [USAN:INN:BAN:JAN]
IFOSFAMIDE/MESNA KIT
Ifosfamidum
Ifosfamidum [INN-Latin]
Ifsofamide
Iphosphamid
Iphosphamid(e)
Iphosphamide
Iso Endoxan
Iso-Endoxan
Isoendoxan
Isofosfamide
Isophosphamide
LS-102
LS-99799
Mitoxana
MJF 9325
MJF-9325
MLS002154021
N,3-Bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
N,3-bis(2-chloroethyl)-2-oxo-1-oxa-3-aza-2$l^{5}-phosphacyclohexan-2-amine
N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide
N,N-Bis(beta-chloroethyl)-amino-N',O-propylene-phosphoric acid ester diamide
N-(2-Chloraethyl)-N'-(2-chloraethyl)-N',O-propylen-phosphorsaureester-diamid [German]
N-(2-Chloroethyl)-N'-(2-chloroethyl)-N',O-propylen ephosphoric acid diamide
N-(2-Chloroethyl)-N'-(2-chloroethyl)-N',O-propylene phosphoric acid ester diamide
N-(2-Chloroethyl)-N'-(2-chloroethyl)-N',O-propylenephosphoric acid diamide
N-(2-Chloroethyl)-N'-(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide
N-(2-Chloroethyl)-N-(3-(2-chloroethyl)-2-oxido-1,3,2-oxazaphosphinan-2-yl)amine
Naxamide
NCGC00016639-01
NCGC00179435-01
NCI-C01638
NCI60_000233
NSC 109,724
NSC 109724
NSC-109,724
NSC-109724
NSC109,724
NSC109724
Prestwick0_000833
Prestwick1_000833
Prestwick2_000833
Prestwick3_000833
SMR001233348
SPBio_002706
WLN: T6NPOTJ AM2G BO B2G
Z 4942
Z-4942
Z4942
{3-(2-Chloroethyl)-2-[(2-
{3-(2-Chloroethyl)-2-[(2-chloroethyl)amino]perhydro-2H-1,3,} 2-oxazaphosphorine oxide
ATC-Codes:
Side-Effects:
Side-EffectFrequency
auditory hallucinations0
siadh0
nephrogenic diabetes insipidus0
pulmonary fibrosis0
dysuria0
pyrexia of unknown origin0
encephalopathy0
confusion0
seizures0
peripheral neuropathy0
vomiting0
renal tubular acidosis0
asthenia0
dermatitis0
hypotension0
nausea0
thrombophlebitis0
stupor0
allergic reaction0
leukopenia0
cystitis0
infection0
somnolence0
polyneuropathy0
depressive psychosis0
hallucinations0
interstitial pneumonitis0
blurred vision0
coma0
alopecia0
anorexia0
acidosis0
constitutional symptoms0
arrhythmia0
hypersensitivity0
hematemesis0
amenorrhea0
metabolic acidosis0
heart failure0
proteinuria0
hyperaminoaciduria0
pancreatitis0
fever0
hematuria0
hyperpigmentation0
agitation0
generalized seizures0
rickets0
thrombocytopenia0
nephropathy0
arteriosclerosis0
anemia0
renal tumor0
urinary frequency0
encephalitis0
renal failure0
constipation0
dizziness0
stomatitis0
pulmonary edema0
hypertension0
urinary incontinence0
neutropenia0
hemorrhage0
diarrhea0

Target

show target details
Uniprot ID:CP2B6_HUMAN
Synonyms:
CYPIIB6
Cytochrome P450 2B6
P450 IIB1
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

References:

10101149
Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes.. C P Granvil; A Madan; M Sharkawi; A Parkinson; I W Wainer (1999) Drug metabolism and disposition: the biological fate of chemicals display abstract
The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on its N-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R, S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoin N-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6beta-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity.
10534317
Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6. Favorable metabolic properties of R-enantiomer.. P Roy; O Tretyakov; J Wright; D J Waxman (1999) Drug metabolism and disposition: the biological fate of chemicals display abstract
The anticancer prodrug ifosfamide (IFA) contains a chiral phosphorous atom and is administered clinically as a racemic mixture of R and S enantiomers. Animal model studies and clinical data indicate enantioselective differences in cytochrome P-450 (CYP) metabolism, pharmacokinetics, and therapeutic efficacy between the two enantiomers; however, the metabolism of individual IFA enantiomers has not been fully characterized. The role of CYP enzymes in the stereoselective metabolism of R-IFA and S-IFA was investigated by monitoring the formation of both 4-hydroxy (activated) and N-dechloroethyl (DCl) (inactive, neurotoxic) metabolites. In the 4-hydroxylation reaction, cDNA-expressed CYPs 3A4 and 3A5 preferentially metabolized R-IFA, whereas CYP2B6 was more active toward S-IFA. Enantioselective IFA 4-hydroxylation (R > S) was observed with six of eight human liver samples. In the N-dechloroethylation reaction, CYPs 3A4 and 2B6 both catalyzed a significantly higher intrinsic metabolic clearance (V(max)/K(m)) of S-IFA compared with R-IFA. Striking P-450 form specificity in the formation of individual DCl metabolites was evident. CYPs 3A4 and 3A5 preferentially produced (R)N2-DCl-IFA and (R)N3-DCl-IFA (derived from R-IFA and S-IFA, respectively), whereas CYP2B6 correspondingly formed (S)N3-DCl-IFA and (S)N2-DCl-IFA. In human liver microsomes, the CYP3A-specific inhibitor troleandomycin suppressed (R)N2- and (R)N3-DCl-IFA formation by >/=80%, whereas (S)N2- and (S)N3-DCl-IFA formation were selectively inhibited (>/=85%) by a CYP2B6-specific monoclonal antibody. The overall extent of IFA N-dechloroethylation varied with the CYP3A4 and CYP2B6 content of each liver, but was significantly lower for R-IFA (32 +/- 13%) than for S-IFA (62 +/- 17%, n = 8; p
12571232
8242617
Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes.. T K Chang; G F Weber; C L Crespi; D J Waxman (1993) Cancer research display abstract
The present study identifies the specific human cytochrome P-450 (CYP) enzymes involved in hydroxylation leading to activation of the anticancer drug cyclophosphamide and its isomeric analogue, ifosphamide. Substantial interindividual variation (4-9-fold) was observed in the hydroxylation of these oxazaphosphorines by a panel of 12 human liver microsomes, and a significant correlation was obtained between these 2 activities (r = 0.85, P < 0.001). Enzyme kinetic analyses revealed that human liver microsomal cyclophosphamide 4-hydroxylation and ifosphamide 4-hydroxylation are best described by a 2-component Michaelis-Menten model composed of both low Km and high Km P-450 4-hydroxylases. To ascertain whether one or more human P-450 enzymes are catalytically competent in activating these oxazaphosphorines, microsomal fractions prepared from a panel of human B-lymphoblastoid cell lines stably transformed with individual P-450 complementary DNAs were assayed in vitro for oxazaphosphorine activation. Expressed CYP2A6, -2B6, -2C8, -2C9, and -3A4 were catalytically competent in hydroxylating cyclophosphamide and ifosphamide. Whereas CYP2C8 and CYP2C9 have the characteristics of low Km oxazaphosphorine 4-hydroxylases, CYP2A6, -2B6, and -3A4 are high Km forms. In contrast, CYP1A1, -1A2, -2D6, and -2E1 did not produce detectable activities. Furthermore, growth of cultured CYP2A6- and CYP2B6-expressing B-lymphoblastoid cells, but not of CYP-negative control cells, was inhibited by cyclophosphamide and ifosphamide as a consequence of prodrug activation to cytotoxic metabolites. Experiments with P-450 form-selective chemical inhibitors and inhibitory anti-P-450 antibodies were then performed to determine the contributions of individual P-450s to the activation of these drugs in human liver microsomes. Orphenadrine (a CYP2B6 inhibitor) and anti-CYP2B IgG inhibited microsomal cyclophosphamide hydroxylation to a greater extent than ifosphamide hydroxylation, consistent with the 8-fold higher activity of complementary DNA-expressed CYP2B6 with cyclophosphamide. In contrast, troleandomycin, a selective inhibitor of CYP3A3 and -3A4, and anti-CYP3A IgG substantially inhibited microsomal ifosphamide hydroxylation but had little or no effect on microsomal cyclophosphamide hydroxylation. By contrast, the CYP2D6-selective inhibitor quinidine did not affect either microsomal activity, while anti-CYP2A antibodies had only a modest inhibitory effect. Overall, the present study establishes that liver microsomal CYP2B and CYP3A preferentially catalyze cyclophosphamide and ifosphamide 4-hydroxylation, respectively, suggesting that liver P-450-inducing agents targeted at these enzymes might be used in cancer patients to enhance drug activation and therapeutic efficacy.