STUDIES WITH STREPTOZOTOCIN LABELLED WITH (14)C IN DIFFERENT POSITIONS INDICATE THAT ITS RAPID METABOLISM IN RAT ... RESULTS IN METABOLITE DERIVED FROM METHYL BEARING NITROSOUREIDO SIDECHAIN. /SRP: DIAZOMETHANE/
来源:Hazardous Substances Data Bank (HSDB)
代谢
在老鼠尿液中检测到五种尿液代谢物；其中两种是对抗生素的α和β-异构体。
/IN MICE URINE/ FIVE URINARY METABOLITES WERE DETECTED; 2 OF THEM WERE THE ALPHA AND BETA-ANOMERS OF THE ANTIBIOTIC.
Streptozocin and metabolites have a short distribution phase (t1/2 6 min) followed by possibly two elimination phases representing active metabolites (t1/2 beta 3.5 hr, t1/2 gamma 40 hr).
Streptozocin is not orally active. After intravenous administration, it is rapidly cleared from plasma and is undetectable after three hours. Metabolites are detected in plasma for up to 24 hours. The drug concentrates in certain tissues; the liver and kidneys contain the highest levels, and pancreas also concentrates streptozocin. Parent drug and metabolites are eliminated rapidly by the kidney; 60% to 70% of a dose is recovered in urine within four hours. Only 10% to 20% of an excreted dose is parent drug.
Serum aminotransferase elevations occur in up to two-thirds of patients treated with streptozocin, but the abnormalities are generally mild, transient and not associated with symptoms or jaundice. Hepatotoxicity is more common with daily dosing and high doses of streptozocin, but with higher doses renal and hematologic toxicities usually overshadow hepatic injury. There have been two reports of rapidly progressive and fatal acute liver failure in patients treated with streptozocin. In one instance, no other chemotherapy was given, in another fluorouracil was coadministered and the patient presented with fever, anuria, acute hepatitis [ALT 1280, bilirubin 11.9, prothrombin index 10%, eosinophils 2600/ µL] at the end of a 5 day course of treatment. In contrast, there have been no individual published case reports of self-limited clinically apparent liver injury attributed to streptozocin, but it has had limited use, as pancreatic islet cell carcinoma and neuroendocrine tumors are rare.
The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated streptozotocin for carcinogenicity. According to their analysis, the weight-of-evidence for streptozotocin is group B2, which is based on sufficient evidence in animals. No data are available in humans. As a group B2 chemical, streptozotocin is considered probably carcinogenic to humans.
No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans.
IN ALL THESE SPECIES /MICE, RATS, CATS, MONKEYS & DOGS/ STR /STREPTOZOTOCIN/ GIVEN PARENTERALLY ... MARKEDLY CONCENTRATED IN LIVER & KIDNEY; FOR EXAMPLE, IN DOGS ... RETAINED IN LIVER FOR MANY HR AFTER ... NO LONGER ... DETECTED IN BLOOD .
STREPTOZOTOCIN (NSC-85998) WAS RAPIDLY EXCRETED IN URINE OF TREATED MICE; 72% OF AN INJECTED DOSE IN THE 4-HR URINE. FIVE URINARY METABOLITES WERE DETECTED ... .
Following intraperitoneal or IV administration of streptozocin in animals, the drug and its metabolites are rapidly distributed mainly into the liver, kidneys, intestine, and pancreas, with lower concentrations being distributed into skeletal muscle, spleen, lungs, heart, and thymus. Concentrations of the drug or its metabolites in the liver, kidneys, intestine, and pancreas are consistently higher than those in plasma. Streptozocin does not appear to cross the blood-brain barrier in animals or humans; however, in humans, metabolites of streptozocin readily distribute into CSF. ... The drug readily crosses the placenta in monkeys.
METHODS OF TREATING LYMPHOMA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
申请人：ONCOETHIX GmbH
公开号：US20170273988A1
公开（公告）日：2017-09-28
A method of treating lymphoma in a mammal comprises the step of: administering to a patient a pharmaceutical acceptable amount of a compound being a thienotriazolodiazepine compound of the Formula (1) wherein R
1
is alkyl having a carbon number of 1-4, R
2
is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R
3
is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4 or cyano; —NR
5
—(CH
2
)
m
—R
6
wherein R
5
is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R
6
is phenyl or pyridyl optionally substituted by a halogen atom; or —NR
7
—CO—(CH
2
)
q
—R
8
wherein R is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R
8
is phenyl or pyridyl optionally substituted by a halogen atom, and R
4
is —(CH
2
)
a
—CO—NH—R
9
wherein a is an integer of 1-4, and R
9
is alkyl having a carbon number of 1-4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4, amino or a hydroxyl group or —(CH
2
)
b
—COOR
10
wherein b is an integer of 1-4, and R
10
is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof. The lymphoma to be treated is diffuse large B-cell lymphom (DLB-CL) specifically selected from activated B-cell DLBCL (ABC-DLBCL) and germinal B-cell DLBCL (GBC-DLBCL).
