Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D03833 (Indinavir)
242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteinase of human T-cell leukemia virus type-1 (HTLV-1), similar to the proteinase of human immunodeficiency virus type-1 (HIV-1), is a potential target for chemotherapy, since the virus is associated with a number of human diseases. A microtiter plate fluorescent assay was developed for the HTLV-1 and HIV-1 proteinases for direct comparison of the inhibition profiles of the enzymes. It was established that, except for Indinavir, none of the inhibitors designed against the HIV-1 proteinase were able to inhibit the HTLV-1 proteinase in the studied concentration range, while two reduced peptide bond-containing peptides having the sequence of HTLV-1 cleavage sites were inhibitors of the HTLV-1 proteinase. One of these was potent enough to be used for active site titration of the HTLV-1 proteinase.
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PMID:Development of a microtiter plate fluorescent assay for inhibition studies on the HTLV-1 and HIV-1 proteinases. 1515 89

Anti-retroviral therapy promotes clinical, immunologic, and virologic improvement in human immunodeficiency virus-infected patients. Whereas this therapy adversely affects carbohydrate and lipid metabolism, the effects of anti-retroviral drugs on muscle protein synthesis and degradation have not been reported. To examine these processes, we treated C2C12 myocytes with increasing concentrations of the protease inhibitor indinavir for 1 or 2 days. Treatment of myocytes with a therapeutic concentration of indinavir (20 microM) for 24 h decreased basal protein synthesis by 18%, whereas a 42% decline was observed after 48 h. A similar decrement, albeit quantitatively smaller, was detected with other protease inhibitors. Indinavir did not alter the rate of proteolysis. Likewise, indinavir did not impair the anabolic effect of insulin-like growth factor-I on protein synthesis. Mechanistically, indinavir decreased the phosphorylation of the S6 ribosomal protein (rpS6), and this reduction was associated with a decreased phosphorylation of p70S6 kinase and p90rsk as well as the upstream regulators ERK1/2 and MEK1/2. Indinavir also decreased the phosphorylation of Mnk1 and its upstream effectors, p38 MAPK and ERK1/2. Indinavir did not affect the phosphorylation of mTOR or 4E-BP1, but it did decrease the amount of the active eukaryotic initiation factor eIF4G-eIF4E complex. In conclusion, indinavir decreased protein synthesis in myocytes. This decrease was associated with the disruption of the ERK1/2 and p38 MAPK pathways and a reduction in both the level of functional eIF4F complex and rpS6 phosphorylation.
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PMID:Indinavir impairs protein synthesis and phosphorylations of MAPKs in mouse C2C12 myocytes. 1522 2

Indinavir is currently used at a fixed dose of 800 mg either three times a day or twice a day in combination with 100 mg of ritonavir. Dosage individualization based on plasma concentration monitoring might, however, be indicated. This study aimed to assess the pharmacokinetic profile of indinavir in patients infected with human immunodeficiency virus to characterize interpatient and intrapatient variability and to build up a Bayesian approach for dosage adaptation. A population analysis was performed with the NONMEM computer program with 569 plasma samples from a cohort of 239 unselected patients receiving indinavir. A one-compartment model with first-order absorption was adapted, and the influences of clinical characteristics on oral clearance (CL) and distribution volume (V) were examined. Predicted average drug exposure and trough and peak concentrations were derived for each patient and correlated with efficacy and toxicity markers. The population estimates of CL were 32.4 liters/h for female and 42.0 liters/h for male patients; oral V was 65.7 liters; and the rate constant of absorption (K(a)) was 1.0 h(-1). CL decreased by 63% with ritonavir intake and was moderately correlated to body weight. Both interpatient variability, best assigned to oral CL (coefficient of variation [CV], 39%) and K(a) (CV, 67%), and intrapatient variability were large (CV, 41%; standard deviation, 670 microg/liter). In conclusion, initial indinavir dosage should be decided according to ritonavir intake and sex, prior to plasma concentration measurements. The high interpatient pharmacokinetic variability represents an argument for therapeutic drug monitoring.
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PMID:Population pharmacokinetics of indinavir in patients infected with human immunodeficiency virus. 1532 77

Highly active antiretroviral therapy (HAART), that includes human immunodeficiency virus (HIV) protease inhibitors (PIs), has been remarkably efficacious including against some opportunistic infections. In this report we investigated the effect(s) of the PI indinavir on protease activity by Cryptococcus neoformans, an opportunistic fungal pathogen responsible for recurrent meningoencephalitis in AIDS patients. Indinavir was also tested for potential effects on other parameters, such as fungal viability, growth ability and susceptibility to immune effector cells. It was found that indinavir impaired cryptococcal protease activity in a time- and dose-dependent fashion. The phenomenon was similarly detectable in ATCC/laboratory strains and clinical isolates. C. neoformans growth rate was also significantly reduced upon exposure to indinavir, while fungal viability was not affected and mitochondrial toxicity not detected. Furthermore, as assessed by an in vitro infection model, indinavir significantly and consistently augmented C. neoformans susceptibility to microglial cell-mediated phagocytosis and killing. Overall, by providing the first evidence that indinavir directly affects C. neoformans, these data add new in vitro insights on the wide-spectrum efficacy of PIs, further arguing for the clinical relevance of HAART against opportunistic infections in AIDS.
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PMID:The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogen Cryptococcus neoformans. 1536 3

Indinavir selectively inhibited production of some virulence factors of Cryptococcus neoformans, such as urease and protease, but not melanin and phospholipase; moreover, it interfered with capsule formation. These effects led to increased susceptibility of C. neoformans to intracellular killing by natural effector cells. Prolonged incubation with indinavir resulted in inhibition of fungal growth. Indinavir can attenuate the virulence of the fungus, thus augmenting its susceptibility to the antimicrobial activity of natural effector cells. The reduction in cryptococcal infections in human immunodeficiency virus-positive patients might also be related to the antifungal activity of highly active antiretroviral therapy.
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PMID:Influence of indinavir on virulence and growth of Cryptococcus neoformans. 1560 42

The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae (n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [(3)H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [(3)H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ (P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 +/- 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 +/- 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 +/- 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 +/- 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.
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PMID:Differential bidirectional transfer of indinavir in the isolated perfused human placenta. 1572 98

The objectives of this study were to build a population pharmacokinetic model that describe plasma concentrations of indinavir in human immunodeficiency virus (HIV)-infected patients with sustained virological response under a stable antiretroviral combination, and to characterize the effect of covariates and co-medications on indinavir pharmacokinetics. Data were obtained from 45 patients who received different dosages of indinavir: either indinavir alone t.i.d. (mostly 800 mg), either indinavir b.i.d. (mostly 800 mg) with a booster dose of 100 mg of ritonavir. Patients were required to have a baseline plasma HIV RNA <200 copies/mL and to have unchanged antiretroviral treatment for 6 months. Indinavir concentrations were measured at a first visit (one sample before drug administration and five after) and at a second visit 3 months later (before and 1 or 3 h after drug administration). A one-compartment model with first-order absorption and first-order elimination best described indinavir pharmacokinetics. For patients treated with indinavir alone, absorption rate constant was estimated to be 0.43/h, and oral clearance Cl/F was 33 L/h. For patients treated with indinavir plus ritonavir these estimates were 0.25/h and 19 L/h, respectively. Cl/F was found to increase by 1.45-fold in men and by 1.18-fold in patients also receiving zidovudine. Oral volume of distribution (V/F) was 24 L. The inter-individual and intra-individual variability were 117 and 205% for V/F, 42 and 58% for Cl/F, respectively. This population analysis in patients with sustained virological response, quantified the effect of ritonavir on the absorption rate constant and on the clearance of indinavir, showed an increase of Cl/F in men and can be used to draw reference curve for therapeutic drug monitoring.
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PMID:Population pharmacokinetic analysis of indinavir in HIV-infected patient treated with a stable antiretroviral therapy. 1591 Jun 62

A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development.
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PMID:Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors. 1643 40

Indinavir sulfate is an inhibitor of the human immunodeficiency virus (HIV) protease. The aim of this study was to determine indinavir levels in serum and pharmaceuticals, by means of electrochemical methods using the hanging mercury drop electrode (HMDE). Indinavir exhibited irreversible cathodic waves over the pH range 2.00-12.00 in different supporting electrolytes. The current-concentration plot was rectilinear over the range from 8 x 10(-7) M to 8 x 10(-6) M with a correlation coefficient of 0.996 for differential pulse voltammetry (DPV) and 8 x 10(-7) M to 1 x 10(-5) M with correlation of 0.999 M for osteryoung square ware voltammetry (OSWV) in Britton-Robinson buffer at pH 10.00. The wave was characterized as being irreversible and diffusion-controlled. The proposed methods were fully validated and successfully applied to the determination of indinavir in capsules and spiked human serum samples with good recoveries. The repeatability and reproducibility of the methods as well as precision and accuracy (such as supporting electrolyte, serum samples) were determined. No electroactive interferences from the endogenous substances were found in serum samples.
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PMID:Electrochemical methods for determination of the protease inhibitor indinavir sulfate in pharmaceuticals and human serum. 1672 36

The effect of p-glycoprotein inhibition on tissue distribution of indinavir, an anti-HIV (human immunodeficiency virus) protease inhibitor drug, has been evaluated. Indinavir was co-administered intravenously in rats along with a p-glycoprotein inhibitor, PSC833, and the drug concentrations in plasma and various tissues were determined using a HPLC method. Additionally, initial uptake clearance of indinavir was evaluated in the brain and testes. The highest increasing effect of p-glycoprotein inhibition on the tissue uptake ratios of indinavir was found in central nervous system (CNS). The estimated tissue extraction the drug was indicative of (i) limited drug entry to brain parenchyma, which was increased significantly by p-glycoprotein inhibition, (ii) non-restricted drug entry to testes, heart and spleen, which was increased significantly in the case of heart and decreased in the case of testes and spleen as a result of p-glycoprotein inhibition, and (iii) drug accumulation in liver and small intestine and, to a lesser extent, kidney, which was not affected by p-glycoprotein inhibition. The uptake clearances of indinavir by brain parenchyma in PSC833-treated and control rats were 68.80+/-8.65 and 21.63+/-4.28 micro/min/g and the corresponding values for the testes were 39.84+/-4.90 and 36.65+/-2.54 microl/min/g. The difference was significant only in the case of brain parenchyma (P<0.001). These data showed that p-glycoprotein inhibition increases the CNS uptake of indinavir markedly and has some transient minor effects on drug uptake by some other tissues.
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PMID:Role of P-glycoprotein in tissue uptake of indinavir in rat. 1679 66


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