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Antimicrobials during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Saquinavir is a protease inhibitor used to treat HIV infection. It is an FDA pregnancy risk category B drug. The Antiretroviral Registry reported 182 first trimester pregnancies exposed to saquinavir, and the frequency of birth defects was not significantly increased (Antiretroviral Registry, 2018). The Registry states that the sample is not sufficiently large to exclude a possible effect from its use during pregnancy. However, if an effect exists, it must be small.
Vitamin C Alimentation via SLC Solute Carriers
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Damian Nydegger, Gergely Gyimesi, Matthias A. Hediger
SVCT1 and SVCT2 are promising drug transporters. SVCT2 may be exploited to facilitate the delivery of certain drugs to the brain via the choroid plexus. For example, nipecotic acid, a γ-aminobutyric acid (GABA) uptake inhibitor, was reported to be transported by SVCT2 when conjugated to 6-Br-ascorbic acid [2]. Saquinavir is a protease inhibitor used in the treatment of HIV. It has a high anti-HIV potency but a low bioavailability. A new prodrug, ascorbyl-succinic-saquinavir, was shown to increase absorptive permeability and metabolic stability. This prodrug was transported by SVCT2 in Caco-2 cells, which could be a potent drug delivery mechanism for anti-HIV protease inhibitors [77]. Ascorbic acid in combination with SVCT2 can also be used as a targeting agent for nanocarriers to transport drugs [2]. Overall, especially SVCT2 with its broad tissue distribution is a promising drug transporter for drugs linked to ascorbic acid or 6-Br-ascorbic acid.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Saquinavir is a potent HIV-1 and HIV-2 protease inhibitor with an IC90 of 20 nM used in the treatment of HIV-1 infection. Fitzsimmons and Collins (1997) have shown that saquinavir is oxidized by both human hepatic and small-intestinal microsomes to two major metabolites (M2 and M7) and five minor metabolites (M1, M3, M4, M5, and M6), with CYP3A4 being the predominant enzyme for its metabolism (Figure 3.84). M2, M3, and M7 are identified as monohydroxylated products resulting from hydroxylation on the octahydro-2-(1H)-iso-quinolinyl (M2 and M3) and (1,1-dimethylethyl)amino (M7) groups. M4, M5, and M6 are identified as monohydroxylated products, but the site of oxidation is yet to be determined (Fitzsimmons and Collins 1997). M7 is further oxidized to the dihydroxylated metabolite M1. Recombinant CYP3A4 forms all metabolites, while incubation with recombinant CYP2D6 showed the formation of an unidentified metabolite (Fitzsimmons and Collins 1997). Eagling et al. (2002) have identified 11 metabolites from incubation of saquinavir with human liver microsomes, most of which are mono- or dihy-droxylated metabolites. CYP3A4 is the predominant enzyme for the formation of all these metabolites. They also identified one of the metabolites as 6-equatorial-hydroxysaquinavir.
Recent advances in nanoformulation development of Ritonavir, a key protease inhibitor used in the treatment of HIV-AIDS
Published in Expert Opinion on Drug Delivery, 2022
Srinivas Reddy Jitta, Navya Ajitkumar Bhaskaran, Shirleen Miriam Marques, Lalit Kumar
Saquinavir is the first-ever protease inhibitor for the treatment of HIV, approved by the US Food and Drug Administration (US FDA). Saquinavir has very poor solubility in the aqueous phase, and its solubility is highly pH-dependent. Along with poor solubility, metabolism by hepatic and small intestinal enzymes are the main reasons for the poor bioavailability [40–42]. Second-generation protease inhibitors used in the treatment of HIV, such as Darunavir, are associated with low oral bioavailability, adverse effects such as liver toxicity and skin rashes. High lipophilic nature, low water solubility, and first-pass metabolism are the major factors for low oral bioavailability [43,44]. Indinavir, a specific protease inhibitor used to treat HIV infection, belongs to BCS class IV with low permeability and low solubility. Clinical application of this drug is limited by low gastrointestinal absorption, short half-life, and extensive hepatic first-pass metabolism [1,45]. Nelfinavir mesylate is an HIV protease inhibitor and an important integral component of highly active antiretroviral therapy (HAART) used in the treatment of AIDS [46]. Lopinavir, a protease inhibitor used in the treatment of HIV, and this drug block the ability of HIV protease to cleave polyprotein resulting in the formation of noninfectious immature virions [38]. Lopinavir exhibits poor oral bioavailability as it is a substrate for the P-gp system and CYP 3A4 present in both intestine and liver [38,47].
Drug delivery to the intestinal lymph by oral formulations
Published in Pharmaceutical Development and Technology, 2022
Takayuki Yoshida, Hiroyuki Kojima, Kazuhiro Sako, Hiromu Kondo
In patients with HIV/AIDs, large numbers of HIV infect CD4+ T lymphocytes in GALT, and the lymphatic system is the primary site of HIV replication (Griffin and O’Driscoll 2006; Gibaud and Attivi 2012). Oral delivery of anti-HIV drugs such as saquinavir to GALT may increase their efficacies with reduced adverse effects. Saquinavir is an orally administered inhibitor of the HIV protease, which causes gastrointestinal disorders, diarrhea, nausea, and bronchitis (Walmsley et al. 2009). Fortovase is the commercially available formulation of saquinavir, which comprises medium-chain mono- and diglycerides/α-tocopherol/povidone (Gibaud and Attivi 2012). Fatty meals increase the oral bioavailability of the formulation in patients (Gibaud and Attivi 2012), suggesting the lymphatic transport of saquinavir via the chylomicron pathway.
Antiviral drugs for coronavirus disease 2019 (COVID-19): a systematic review with network meta-analysis
Published in Expert Review of Anti-infective Therapy, 2022
George N. Okoli, Rasheda Rabbani, Amenah Al-Juboori, Leslie Copstein, Nicole Askin, Ahmed M. Abou-Setta
Following the WHO recommendation of evaluating potential COVID-19 drugs through large multinational randomized controlled trials (RCTs) [17], a multicenter global RCT [15], showed shortened time to recovery in hospitalized patients with remdesivir; leading it to become the first approved drug by the United States (USA) Food and Drug Administration (FDA) for the treatment of severe hospitalized COVID-19 patients [18]. However, an interim report from another multinational RCT [19] in hospitalized COVID-19 patients found that there was no difference in mortality between remdesivir and usual clinical care. Studies aimed at identifying potential inhibitors against SARS-CoV-2 main proteinase (Mpro) explored various FDA-approved drugs such as darunavir, indinavir, saquinavir, tipranavir, raltegravir, velpatasvir, and ledipasvir identified as potential candidates for the treatment of COVID-19 in some previous docking studies involving monomeric SARS-CoV2 Mpro [20]. Saquinavir was identified as a potent inhibitor of dimeric SARS-CoV2 Mpro and may have clinical utility against COVID-19 [20,21]. Studies on other antiviral drugs have revealed largely conflicting findings.