Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug-drug interactions involving induction of cytochrome P450 enzymes (P450s) can lead to loss of drug efficacy. Certain drugs, particularly those used to treat mycobacterial and human immunodeficiency virus (HIV) infections, are especially prone to induce P450s. During studies to examine drug-interaction potential of compounds in cultured human hepatocytes, exposure with (S)-1-[(1S,3S,4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3,3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)-pentylcarbamoyl]-2,2-dimethyl-propyl-carbamic acid methyl ester (A-792611), a novel HIV protease inhibitor (PI) previously under investigation for the treatment of HIV infection, resulted in significant down-regulation of constitutive CYP3A4 expression. Furthermore, coadministration of A-792611 was found to attenuate CYP3A4 induction mediated by known inducers rifampin and efavirenz. A-792611 also attenuated the rifampin and ritonavir-mediated activation of the human pregnane X receptor (PXR) in luciferase reporter assays. Microarray analysis on cultured human hepatocytes revealed that A-792611 treatment down-regulated the expression of PXR target genes CYP3A4, CYP2B6, CYP2C8, and CYP2C9, whereas there was a lack of inductive effect observed in treated rat hepatocytes. A-792611 did not interact with other ligand-activated nuclear receptors that regulate P450 expression such as constitutive androstane receptor, farnesoid X receptor, vitamin D receptor, and peroxisome proliferator-activated receptor alpha. These data suggest that A-792611 is a functional and effective human PXR inhibitor. Among the class of HIV-PIs, which are typically PXR activators, A-792611 seems to have a unique property for PXR antagonism and could be a useful tool for studying nuclear receptor pathway regulation.
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PMID:A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane X receptor. 1809 73

The success of antiretroviral therapy leads to a chronification of HIV-infection resulting in a decline of lethality. The lifelong intake of antiinfectives, though, may result in drug side effects with clinical dental implications. Despite fundamental cellular alterations, including prolonged hemorrhage following surgical interventions, antiretrovirals of all classes, of protease inhibitors, (non-nucleoside) reverse transcriptase inhibitors and of fusion inhibitors may promote oral manifestions like oral ulcera, dysgeusia, salivary gland disorders, papilloma, (peri)oral paresthesia or aphtous stomatitis. Due to inhibitory effects especially of protease inhibitors of cy tochrome P450-isoenzyme CYP3A4 therapeutical interactions with psychotropics/sedatives, antifungal agents, corticoids and intiinfectives, particularly metronidazole, may raise. The application and prescription of systemically metabolized adjuvant drugs as well as the monitoring of the possible progression of HIV infection is a key task in the oral health care of HIV-seropositive patients calling for a close medical coordination of therapeutical interventions.
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PMID:[Implications of antiretroviral therapy in oral medicine--a review of literature]. 1822 98

HIV-infected patients in sub-Saharan countries highly depend on traditional medicines for the treatment of opportunistic oral infections as candidiasis. Previous investigations on antifungal activity of medicinal plant extracts utilized by traditional healers in Tanzania have revealed 12 extracts with potent antifungal activity. Although the plants may be good candidates for new treatment opportunities, they can be toxic or genotoxic and could cause pharmacokinetic interactions when used concomitantly with antiretroviral agents. Therefore, we investigated the cytotoxicity, genotoxicity and cytochrome P450 interaction potential of these medicinal plants. Cytotoxicity was tested by Hoechst 33342, Alamar Blue, calcein-AM, glutathione depletion and O(2)-consumption assays and genotoxicity by a Vitotox assay. Competition of the 12 extracts on substrate metabolism by CYP3A4, 2C9, 2C19 and 2D6 was tested with high-throughput CYP inhibition screening. Pregnane X receptor (PXR) activation was tested using Chinese hamster ovary cell lines expressing human PXR. Herbal extracts inducing high human PXR activation were tested for enhanced CYP3A4 mRNA levels with quantitative polymerase chain reaction. Genotoxicity was found for Jatropha multifida, Sterculia africana and Spirostachys africana. All plant extracts showed high cytotoxic effects in almost all tests. Potent competition with CYP3A4, 2D6, 2C9 and 2C19 was found for 75% of the herbal extracts. Spirostachys africana did not affect CYP2D6 and for S. africana and Turraea holstii no effect on CYP2D6 and CYP3A4 (DBF) was found. Nine plant extracts showed significant activation of human PXR, but only Agaura salicifolia, Turraea holstii and S. africana significantly induced CYP3A4 mRNA levels. These results indicate the possibility of potential medicinal plant-antiretroviral interactions.
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PMID:Evaluation of cytotoxic, genotoxic and CYP450 enzymatic competition effects of Tanzanian plant extracts traditionally used for treatment of fungal infections. 1833 92

Human cytochrome P450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% marketed drugs. The crystal structure of bound and unbound CYP3A4 has been recently constructed, and a small active site and a peripheral binding site are identified. A recent study indicates that CYP3A4 undergoes dramatic conformational changes upon binding to ketoconazole or erythromycin with a differential but substantial (>80%) increase in the active site volume, providing a structural basis for ligand promiscuity of CYP3A4. A number of important drugs have been identified as substrates, inducers and/or inhibitors of CYP3A4. The ability of drugs to act as inducers, inhibitors, or substrates for CYP3A is predictive of whether concurrent administration of these compounds with a known CYP3A substrate might lead to altered drug disposition, efficacy or toxicity. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein (P-gp). To date, the identified clinically important CYP3A4 inhibitors mainly include macrolide antibiotics (e.g., clarithromycin, and erythromycin), anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), steroids and their modulators (e.g., gestodene and mifepristone), and several herbal and dietary components. Many of these drugs are also mechanism-based inhibitors of CYP3A4, which involves formation of reactive metabolites, binding to CYP3A4 and irreversible enzyme inactivation. A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. The orphan nuclear receptor, pregnane X receptor (PXR), have been found to play a critical role in the induction of CYP3A4. The inhibition or induction of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs and the patients. The study of interactions of newly synthesized compounds with CYP3A4 has been incorporated into drug development and detection of possible CYP3A4 inhibitors and inducers during the early stages of drug development is critical in preventing potential drug-drug interactions and side effects. Clinicians are encouraged to have a sound knowledge on drugs that behave as substrates, inhibitors or inducers of CYP3A4, and take proper cautions and close monitoring for potential drug interactions when using drugs that are CYP3A4 inhibitors or inducers.
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PMID:Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. 1847 49

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.
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PMID:Etravirine for the treatment of HIV infection. 1866 9

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.
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PMID:Clinical drugs that interact with St. John's wort and implication in drug development. 1867 95

Maraviroc (MVC, Celsentri) is an allosteric and reversible inhibitor of the CCR5 chemokine coreceptor. MVC is the first marketed CCR5 antagonist and the only oral entry inhibitor approved so far for the treatment of HIV infection. It has been approved for adults with previous antiretroviral exposure. MVC exclusively inhibits the replication of R5- tropic HIV-1 variants after binding to the transmembrane CCR5 receptor cavity. MVC is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5- 4 hours after a 300 mg dose. Renal clearance is approximately 10-12 L/h. MVC is a substrate of the cytochrome P450 isoenzyme 3A4; therefore dose adjustments are required when co-administrated with other drugs that induce or inhibit CYP3A4. In addition, MVC dose adjustments are advised in patients with renal failure (CLcr <80 ml/min) only if they receive CYP3A4 inhibitors.
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PMID:[Pharmacokinetics, interactions and mechanism of action of maraviroc]. 1913 16

The treatment of HIV is often complicated by the emergence of antiretroviral (ARV) resistance, which has prompted the development of ARV drugs with novel mechanisms of action and resistance profiles. One of the newest classes of ARVs is the integrase inhibitors. These agents inhibit viral replication by preventing integration of viral DNA into the host cell. Japan Tobacco Inc and Gilead Sciences Inc are developing elvitegravir, a novel integrase inhibitor undergoing phase III clinical trials. Elvitegravir is predominantly metabolized via cytochrome P450 (CYP)3A4, along with minor pathways including glucuronidation via UGT1A1/3 and oxidative metabolism. Consequently, the coadministration of elvitegravir with the protease inhibitor ritonavir (a substantial CYP3A4 inhibitor) results in significantly enhanced bioavailability and a longer half-life than with elvitegravir alone, allowing for the once-daily dosing of elvitegravir. In vitro and clinical data suggest that elvitegravir has an overlapping resistance profile with raltegravir and with other integrase inhibitors that are in development. Data from phase I/II clinical trials have demonstrated excellent virological responses with elvitegravir, as well as minimal toxicities. At the time of publication, phase III trials to examine the efficacy and toxicity of elvitegravir were enrolling patients infected with HIV-1.
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PMID:Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection. 1919 97

South Africa, like many other Southern African countries, has one of the highest HIV infection rates in the world and many individuals consequently receive antiretroviral therapy (ART). However, knowledge regarding (i) the prevalence of functional single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes, and (ii) variance in pharmacotherapy both within and between different populations and ethnic groups is limited. The aim of this study was to determine whether selected polymorphisms in cytochrome P450 (CYP) genes (CYP2B6 and CYP3A4) and the multidrug-resistance 1 (ABCB1) gene underlie altered antiretroviral (ARV) drug response in two South African populations. DNA samples from 182 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity on ART were genotyped for the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in ABCB1. Univariate two-way analysis of variance (ANOVA) testing revealed no apparent effect of ethnicity on immune recovery (in terms of CD4-cell count) in response to ART. Univariate one-way ANOVA testing revealed a discernible effect of genotype on immune recovery in the cases of the T-129C (P=0.03) and G2677A (P<0.01) polymorphisms in the ABCB1 gene. This study serves as a basis for better understanding and possible prediction of pharmacogenetic risk profiles and drug response in individuals and ethnic groups in South Africa.
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PMID:A pharmacogenetic study of CD4 recovery in response to HIV antiretroviral therapy in two South African population groups. 1928 74

Nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, has been associated with incidences of skin rash and hepatotoxicity in patients. Although the mechanism of idiosyncratic hepatotoxicity remains unknown, it is proposed that metabolic activation of nevirapine and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether nevirapine undergoes cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. Liquid chromatography-tandem mass spectrometry analysis of incubations containing nevirapine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed the formation of a GSH conjugate derived from the addition of the sulfydryl nucleophile to nevirapine. No other GSH conjugates were detected, including conjugates of oxidized metabolites of nevirapine. These findings are consistent with a bioactivation sequence involving initial P450-catalyzed dehydrogenation of the aromatic nucleus with a 4-methyl group in nevirapine to an electrophilic quinone methide intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugate. Formation of the nevirapine GSH conjugate was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP2D6, CYP2C19, and CYP2A6. In addition, the quinone methide reactive metabolite was a mechanism-based inactivator of CYP3A4, with inactivation parameters K(I) = 31 microM and k(inact) = 0.029 min(-1), respectively. It is proposed that formation of the quinone methide intermediate may represent a rate-limiting step in the initiation of nevirapine-mediated hepatotoxicity.
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PMID:Metabolic activation of nevirapine in human liver microsomes: dehydrogenation and inactivation of cytochrome P450 3A4. 1936 30


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