Saquinavir is extensively metabolized in the liver following oral administration, and _in vitro_ studies have shown that >90% of its biotransformation is mediated by the CYP3A4 isoenzyme. Saquinavir is rapidly metabolized to a number of inactive mono- and di-hydroxylated compounds.
Results of in vitro studies indicate that saquinavir is rapidly metabolized in the liver to several monohydroxylated and dihydroxylated inactive metabolites. Metabolism of saquinavir is mediated by cytochrome P450; the isoenzyme CYP3A4 is involved in more than 90% of this metabolism. Orally administered saquinavir appears to undergo substantial metabolism on first pass through the liver.
Saquinavir has known human metabolites that include (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-7-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-[(1-hydroxy-2-methylpropan-2-yl)carbamoyl]-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, and (2S)-N-[(2S,3R)-4-[(3S,4aR,8aS)-3-(tert-butylcarbamoyl)-6-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide.
Some degree of serum aminotransferase elevations occur in a high proportion of patients taking saquinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication.
Clinically apparent liver injury from saquinavir is rare, and the clinical pattern of liver injury, latency and recovery have not been well defined. However, several other HIV protease inhibitors have been associated with symptomatic acute liver injury for which the clinical pattern has been defined. The injury usually arises 1 to 8 weeks after onset and has variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation. The injury is usually self-limited and resolves rapidly upon stopping the implicated protease inhibitor (Case 1).
Saquinavir has also been associated with a rapid onset (1 to 4 days) acute hepatic injury in patients who are taking rifampin and perhaps other agents that affect hepatic CYP 450 activity, such as phenobarbital (Case 1). This syndrome has the appearance of direct hepatotoxicity with acute hepatic necrosis. Jaundice is rare and the injury resolves rapidly once saquinavir is stopped. The cause of this rapid onset syndrome is unknown, but is probably caused by drug-drug interactions.
Finally, initiation of saquinavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and concurrent increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. These exacerbations of chronic viral hepatitis may represent immune reconstitution syndrome and can occur with initiation of any potent antiretroviral regimen. Saquinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.
Likelihood score: D (Possible rare cause of clinically apparent liver injury).
The absolute bioavailability of orally administered saquinavir is only ~4%, thought to be a consequence of incomplete absorption and extensive first-pass metabolism. It is co-administered with ritonavir, another protease inhibitor and a potent inhibitor of the enzymes responsible for saquinavir's first-pass metabolism, in order to dramatically boost its serum concentrations and, by extension, its therapeutic efficacy. Following administration of saquinavir 1000mg twice daily with ritonavir 100mg twice daily the AUC24h at steady-state was 39026 ng.h/mL.
The primary means of elimination of saquinavir appears to be extensive hepatic metabolism followed by fecal excretion of both the parent drug and metabolic products. Following the administration of radiolabeled saquinavir (both orally and intravenously), approximately 81-88% of radioactivity is recovered in the feces within 5 days of dosing while only 1-3% is recovered in the urine. Mass balance studies indicate that only 13% of orally-administered plasma radioactivity is attributed to unchanged parent drug, with the remainder comprising metabolic products of saquinavir's hepatic metabolism. In contrast, intravenous administration resulted in approximately 66% of the circulating plasma radioactivity being attributed to unchanged parent drug, suggesting a high degree of first-pass metabolism with oral administration.
来源:DrugBank
吸收、分配和排泄
分布容积
稳态分布容积约为700升，这表明组织广泛分布。
The steady-state volume of distribution of saquinavir is approximately 700 L, suggesting extensive distribution into tissues.
来源:DrugBank
吸收、分配和排泄
清除
静脉给药后，沙奎那韦的系统清除率大约为1.14 L/h/kg。
The systemic clearance of saquinavir is approximately 1.14 L/h/kg following intravenous administration.
Following administration of saquinavir in a dosage of 1200 mg 3 times daily as liquid-filled capsules, mean steady-state AUC at 3 weeks was 7249 ngh/mL compared with an AUC of 866 ngh/mL reported following administration of saquinavir hard gelatin capsules in a dosage of 600 mg 3 times daily. While the AUC of saquinavir in adults receiving liquid-filled capsules was lower at week 61-69 compared with the AUC at week 3, the AUC at week 61-69 was greater than the AUC at the same time point in HIV-infected adults receiving saquinavir as hard gelatin capsules (600 mg 3 times daily).
Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies
摘要：
Systemic lupus erythematosus is an autoimmune disease that can affect numerous tissues and is characterized by the production of nuclear antigen-directed autoantibodies (e.g., anti-dsDNA). Using a combination of virtual and ELISA-based screens, we made the intriguing discovery that several HIV-protease inhibitors can function as decoy antigens to specifically inhibit the binding of anti-dsDNA antibodies to target antigens such as dsDNA and pentapeptide DWEYS. Computational modeling revealed that HIV-protease inhibitors comprised structural features present in DWEYS and predicted that analogues containing more flexible backbones would possess preferred binding characteristics. To address this, we reduced the internal amide backbone to improve flexibility, producing new small-molecule decoy antigens, which neutralize anti-dsDNA antibodies in vitro, in situ, and in vivo. Pharmacokinetic and SLE model studies demonstrated that peptidomimetic FISLE-412,(1) a reduced HIV protease inhibitor analogue, was well-tolerated, altered serum reactivity to DWEYS, reduced glomeruli IgG deposition, preserved kidney histology, and delayed SLE onset in NZB/W F1 mice.
PROCESS FOR SYNTHESIS OF SYN AZIDO EPOXIDE AND ITS USE AS INTERMEDIATE FOR THE SYNTHESIS OF AMPRENAVIR & SAQUINAVIR
申请人：Council of Scientific & Industrial Research
公开号：US20150011782A1
公开（公告）日：2015-01-08
Disclosed herein is a novel route of synthesis of syn azide epoxide of formula 5, which is used as a common intermediate for asymmetric synthesis of HIV protease inhibitors such as Amprenavir, Fosamprenavir, Saquinavir and formal synthesis of Darunavir and Palinavir obtained by Cobalt-catalyzed hydrolytic kinetic resolution of racemic anti-(2SR,3SR)-3-azido-4-phenyl-1,2-epoxybutane (azido-epoxide).
[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.
[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.
[EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020257998A1
公开（公告）日：2020-12-30
Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
