Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT).
Zidovudine is rapidly metabolized via glucuronidation in the liver principally to 3-azido-3-deoxy-5-O-beta-d-glucopyranuronosylthymidine (GZDV; formerly GAZT); zidovudine is also metabolized to GZDV in renal microsomes. GZDV has an apparent elimination half-life of 1 hour (range: 0.6-1.7 hours) and does not appear to have antiviral activity against HIV. In addition, two other hepatic metabolites of zidovudine have been identified as 3-amino-3-deoxythymidine (AMT) and its glucuronide derivative (GAMT). Intracellularly, in both virus-infected and uninfected cells, zidovudine is converted to zidovudine monophosphate by cellular thymidine kinase; the monophosphate derivative is phosphorylated to zidovudine diphosphate via cellular dTMP kinase (thymidylate kinase) and then to zidovudine triphosphate via other cellular enzymes. Intracellular (host cell) conversion of zidovudine to the triphosphate derivative is necessary for the antiviral activity of the drug. Activation for antibacterial action, however, does not depend on phosphorylation within host cells but rather depends on conversion within bacterial cells.
The mechanisms of intestinal mucosal transport and metabolism of zidovudine and other thymidine analogs were studied. No zidovudine metabolites appeared in any part of the gastrointestinal tract. Other thymidine analogs were rapidly metabolized in the upper gastrointestinal tract, but not in the colon.
Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT).
Route of Elimination: As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.
Half Life: Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)
Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5ду_-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase ‘± and ‘_.
Chronic therapy with zidovudine is associated with modest serum enzyme elevations that are generally transient and asymptomatic and do not require dose modification. In prospective studies, 1 to 3% of recipients have developed ALT elevations above 5 times the upper limit of normal. The abnormalities, however, may be related to other underlying conditions such as hepatitis B or C and triggered by reconstitution syndrome.
Several forms of clinically apparent liver injury have been associated with zidovudine therapy: an acute cholestatic hepatitis, severe acute fatty liver and with lactic acidosis, and a chronic liver injury that presents with noncirrhotic portal hypertension, most likely due to nodular regenerative hyperplasia.
Rare instances of idiosyncratic cholestatic hepatitis have been reported with zidovudine therapy, typically arising within 1 to 4 weeks of starting treatment (Case 1). The liver injury is usually mild to moderate in severity and self-limited in course. Immunoallergic and autoimmune features are not common.
In addition, zidovudine has been associated with instances of severe hepatic steatosis and lactic acidosis. The liver injury typically arises after 2 to 6 months of therapy with prodromal symptoms of nausea, vomiting, anorexia and weakness, followed by dyspnea, jaundice and confusion. Lactic acid levels are elevated and metabolic acidosis may be severe and progressive. Serum enzymes are only modestly elevated and may initially be normal. Jaundice and signs of liver dysfunction develop late, but can eventually be associated with acute hepatic failure and death. Liver histology shows marked steatosis which is initially microvesicular and later macrovesicular and associated with cholestasis. In progressive cases, fibrosis and Mallory bodies are found. Similar cases occur with didanosine and stavudine which are more frequent causes of this syndrome. Risk factors for mitochondrial injury due to zidovudine include female sex, older age, preexisting liver disease, obesity, alcohol use and concurrent use of other di-deoxynucleosides.
Finally, long term therapy with zidovudine and other first generation nucleoside analogues has been associated with development of noncirrhotic portal hypertension. Symptoms are typically suggestive of cirrhosis, with fatigue, weight loss, ascites and/or variceal hemorrhage, but liver histology shows little or no fibrosis. Jaundice is uncommon. Laboratory testing demonstrates minor elevations in serum aminotransferase and alkaline phosphatase levels but normal levels of serum bilirubin, albumin and INR. Splenomegaly is common and thrombocytopenia is often the first manifestation of the hepatic abnormalities. Liver biopsies can be deceptively benign, with scant fibrosis and minor nonspecific changes. The disturbed hepatic architecture may not be obvious unless reticulum stains are done that show the typical nodularity and two-cell thick plates characteristic of nodular regeneration. The cause of nodular regenerative hyperplasia is not known but is suspected to be due to chronic vascular injury to the small veins and arterioles in portal areas.
Likelihood score: B (likely cause of clinically apparent acute and chronic liver disease).
Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.
As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.
来源:DrugBank
吸收、分配和排泄
分布容积
表观分布容积，HIV感染患者，静脉注射 = 1.6 ± 0.6 L/kg
Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg
0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.
In patients with impaired renal function, plasma concentrations of zidovudine may be increased and the half-life prolonged. In one study in adults with impaired renal function (creatinine clearances ranging from 6-31 ml/minute) without HIV infections beta half life of zidovudine averaged 1.4 hours and was similar to that reported for adults with HIV infections who had normal renal function. However, the beta half life of glucuronide in these adults with impaired renal function averaged 8 hours and was considerably prolonged compared with that reported for adults with HIV infections who had normal renal function. In one study in adults with hemophilia and HIV infections who had elevated serum concentrations of aspartate aminotransferase (serum glutamic-oxaloacetic transaminase), alanine aminotransferase (serum glutamic-pyruvic transaminase), pharmacokinetics of zidovudine after a single 300 mg oral dose showed considerable interindividual variation.
Hypophosphorous Acid-Iodine: An Efficient and Mild Reagent for Cleavage of N–C Bond
摘要：
A mixture of hypophosphorous acid (H3PO2) and iodine in acetic acid can selectively cleave the N-alkyl bond in a variety of substituted heterocylic compounds in good to excellent yields without any damage to amide bond present in the substrates.
[EN] SPIROCYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES SPIROCYCLIQUES UTILES COMME INHIBITEURS DU VIH
申请人：MERCK SHARP & DOHME
公开号：WO2016094198A1
公开（公告）日：2016-06-16
The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.
Sodium periodate in aqueous organic solvents selectively removes, under mild reaction conditions, the O-(dimethoxytrityl) protecting group. Selectivity of the cleavage was studied using the nucleoside derivatives protected by various types of groups commonly used in nucleoside and nucleotide chemistry.
3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
申请人：Xue Chu-Biao
公开号：US20060004018A1
公开（公告）日：2006-01-05
The present invention is directed to compounds of Formula I:
which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.
[EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2017046658A1
公开（公告）日：2017-03-23
Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
