CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir<i>in vitro</i>

Eagling, V.A.; Wiltshire, Hugh; Whitcombe, Ian; Back, David

doi:10.1080/00498250110085845

Cited by 58 publications

(42 citation statements)

References 17 publications

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“…No literature was identified on in vitro metabolism of ritonavir in rat hepatocytes, but in vivo and microsomal data published by Denissen et al (1997) and Kumar et al (1996) determined that metabolites M1, M2, M9, and M11 were the predominant primary metabolites, which agrees with observations in our work. Studies have been carried out in human liver microsomes at comparable substrate concentrations with the present study, and low K m estimates were reported: 0.61 and, 0.92 M for saquinavir (Eagling et al, 2002) and ritonavir (Koudriakova et al, 1998).…”

Section: Hepatocellular Uptake and Drug Metabolic Clearancementioning

confidence: 99%

Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir

Parker

Houston²

2008

Drug Metab Dispos

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ABSTRACT:The intrinsic metabolic clearance of saquinavir, nelfinavir, and ritonavir was determined over a range of concentrations (0.02-20 M) in both rat liver microsomes and fresh isolated rat hepatocytes in suspension. Clearance values were found to be concentration dependent for both systems, and at low concentrations, microsomal clearance was much greater (7-14-fold) than in hepatocytes. Kinetic parameters showed substantially lower microsomal K m values (5-42 nM) compared with suspended rat hepatocytes (34-270 nM) but similar scaled V max values (2-26 nmol/min/g liver). In the absence of metabolism (achieved by pretreating hepatocytes with a mechanism-based inhibitor of cytochrome P450), saquinavir, nelfinavir, and ritonavir were actively and rapidly taken up into hepatocytes (cell/medium concentration ratios of 306-3352), and intracellular unbound drug concentrations between 5-and 12-fold higher than extracellular unbound concentrations were achieved. Comparison of the rate of uptake into hepatocytes with the rate of metabolism in hepatocytes and microsomes indicates that the former is the rate-limiting step at low concentrations. The rate of metabolism saturates at lower concentrations (100-400-fold) than the rate of uptake; hence, at the high concentrations metabolic rate-limited clearance occurs. In conclusion, the clearance of saquinavir, nelfinavir, and ritonavir is extremely rapid, and it is proposed that in the case of hepatocytes and by inference in vivo, the rate of uptake limits the metabolic clearance of these three drugs.

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Section: Hepatocellular Uptake and Drug Metabolic Clearancementioning

confidence: 99%

Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir

Parker

Houston²

2008

Drug Metab Dispos

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Section: Protease Inhibitors (Pis)mentioning

confidence: 99%

“…Another five minority metabolites were found (Flitzsimmons, Collins, 1997). One of the major metabolites was subsequently identified as 6-equatorial-hydroxy-saquinavir (Eaglings et al, 2002).Biotransformation of indinavir (IDV) (Figure 14) takes place primarily in liver by CYP3A4 Lin et al, 1996), and can also occur in the small intestine. Oxidative metabolites were found in both in vivo and in vitro experiments using liver and intestinal microsomes of humans and rats (Chiba, Hensleigh, Lin, 1997).…”

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Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Andrade

Freitas

Oliveira

2011

Braz. J. Pharm. Sci.

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From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Uniterms: AIDS/treatment. Drugs/anti-HIV. Drugs/metabolism. Antiretroviral drugs. Biotransformation.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica.Unitermos: AIDS/tratamento. Fármacos/anti-HIV. Fármacos/antirretrovirais. Fármacos/metabolismo. Biotransformação. INTRODUCTIONThe human immunodeficiency virus (HIV) has been established as the causative agent of the acquired immunodeficiency syndrome (AIDS) for over twentysix years now (Barré-Sinoussi et al., 1983). During this time, an unprecedented success has been achieved in discovering anti-HIV drugs as reflected by the fact that there are now more drugs approved for the treatment of HIV than for all other viral infections put together (Mehellou, De Clercq, 2009). Despite this progress...

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“…69 Currently, there appears to be a lack of studies demonstrating CYP450 expression in human T cells. As mentioned earlier, we did not detect any SQV degradants/ metabolites using our HPLC method.…”

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confidence: 99%

Novel intravaginal nanomedicine for the targeted delivery of saquinavir to CD4+ immune cells

Yang¹,

Chen²,

Gu³

et al. 2013

IJN

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Abstract:The goal of this study was to develop and characterize an intravaginal nanomedicine for the active targeted delivery of saquinavir (SQV) to CD4+ immune cells as a potential strategy to prevent or reduce HIV infection. The nanomedicine was formulated into a vaginal gel to provide ease in self-administration and to enhance retention within the vaginal tract. SQV-encapsulated nanoparticles (SQV-NPs) were prepared from poly(lactic-co-glycolic acid) (PLGA) and conjugated to antihuman anti-CD4 antibody. Antibody-conjugated SQV-NPs (Ab-SQV-NPs) had an encapsulation efficiency (EE%) of 74.4% ± 3.7% and an antibody conjugation efficiency (ACE%) of 80.95% ± 1.10%. Over 50% of total loaded SQV was released from NPs over 3 days. NPs were rapidly taken up by Sup-T1 cells, with more than a twofold increase in the intracellular levels of SQV when delivered by Ab-SQV-NPs in comparison to controls 1 hour post-treatment. No cytotoxicity was observed when vaginal epithelial cells were treated for 24 hours with drug-free Ab-NPs (1,000 µg/mL), 1% HEC placebo gel (200 mg/mL), or 1% HEC gel loaded with drug-free Ab-NPs (5 mg NPs/g gel, 200 mg/mL of gel mixture). Overall, we described an intravaginal nanomedicine that is nontoxic and can specifically deliver SQV into CD4 + immune cells. This platform may demonstrate potential utility in its application as postexposure prophylaxis for the treatment or reduction of HIV infection, but further studies are required.

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CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavirin vitro

Cited by 58 publications

References 17 publications

Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir

Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Novel intravaginal nanomedicine for the targeted delivery of saquinavir to CD4+ immune cells

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