Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus

Liu, William; Yu, Sarah; Yan, Bingfang

doi:10.1016/j.bcp.2022.115224

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…In humans, CES1 and CES2 are two c arboxyl es terases with known pharmacological and toxicological significance 106–109 . These two carboxylesterases, on the other hand, differ in their substrate specificity and tissue distribution 110–112 . CES1 preferably hydrolyzes esters with an acyl moiety relatively larger than its alkoxy moiety, 96 and opposite is true with CES2 107,108 …”

Section: Metabolism and Active Transportmentioning

confidence: 99%

“…[106][107][108][109] These two carboxylesterases, on the other hand, differ in their substrate specificity and tissue distribution. [110][111][112] CES1 preferably hydrolyzes esters with an acyl moiety relatively larger than its alkoxy moiety, 96 and opposite is true with CES2. 107,108 The isopropylester of molnupiravir has an alkoxy moiety relatively larger than its acyl moiety (boxed in Figure 1).…”

Section: Metabolism Of Molnupiravirmentioning

confidence: 99%

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Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

Yan

2023

Fundamemntal Clinical Pharma

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The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir, and remdesivir has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (M pro ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2), nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4), and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.

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Section: Metabolism and Active Transportmentioning

confidence: 99%

Section: Metabolism Of Molnupiravirmentioning

confidence: 99%

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

Yan

2023

Fundamemntal Clinical Pharma

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Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review

Liu,

Li,

Zhu

2024

Expert Opinion on Drug Metabolism & Toxicology

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Metabolism Pathways of Major Therapeutics for Treating Monkeypox Mono- and Co-infection with Human Immunodeficient Virus or SARS-CoV-2

Yan

2023

CDM

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Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, par¬ticu¬larly of hydrolysis, phospho¬rylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.

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Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus

Cited by 3 publications

References 52 publications

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review

Metabolism Pathways of Major Therapeutics for Treating Monkeypox Mono- and Co-infection with Human Immunodeficient Virus or SARS-CoV-2

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