Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fluconazole inhibits cytochrome P-450-mediated enzymatic metabolism of several drugs. Since hepatic metabolism is partially responsible for 2',3'-dideoxyinosine (didanosine or ddI) elimination, fluconazole therapy may lead to increased ddI concentrations in serum and subsequent concentration-dependent adverse effects. The purpose of this study was to determine if ddI pharmacokinetics are influenced by a 7-day course of oral fluconazole. Twelve adults with human immunodeficiency virus (HIV) who had received a constant dosage of ddI for at least 2 weeks were investigated. On study day 1, multiple serum samples for determination of ddI concentrations were obtained over 12 h. Then subjects received a 7-day course of oral fluconazole (200 mg every 12 h for two doses and then 200 mg once daily for 6 days) while ddI therapy continued. Following the last dose of fluconazole, serum samples for determination of ddI concentrations were again obtained over 12 h. ddI concentrations in serum were analyzed by radioimmunoassay. In contrast to previously published data, there was marked between-subject variability in ddI areas under the concentration-time curve, even when the dose was normalized for weight. No significant differences were found between mean ddI areas under the concentration-time curve from 0 to 12 h on study day 1 (1,528 +/- 902 ngx.hr/ml) and following fluconazole treatment (1,486 +/- 649 ngx.hr/ml) . There were no significant differences in other pharmacokinetic parameters, such as ddI peak concentrations in serum (971 +/- 509 and 942 +/- 442 ng/ml) or half-lives (80 +/- 32 and 85 +/- 21 min.) before and after fluconazole treatment, respectively. We conclude that a 7-day course of oral fluconazole does not significantly alter ddI pharmacokinetics in adults that are infected with human immunodeficiency virus.
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PMID:Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus. 762 87

Patients with AIDS who are receiving optimal medical care, including combination therapy with antiretroviral agents and more effective prophylaxis and therapy for opportunistic infections and neoplasms, are surviving longer. However, the potential for drug interactions in these patients is increased because many of the currently used antibiotics and antiviral agents have profound effects on the hepatic cytochrome P-450 enzyme system, on renal tubular function, and on bone marrow function. In this AIDS Commentary, Dr. Piscitelli and colleagues have succinctly reviewed the current state of our knowledge regarding the potential for additive or synergistic drug interactions that can result in enhanced toxicity or, alternatively, augmented therapeutic benefit. Information on these interactions will become more important as more intensive and effective therapy becomes available for persons with far-advanced infection due to human immunodeficiency virus type 1.
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PMID:Drug interactions in patients infected with human immunodeficiency virus. 933 49

Hypersensitivity reactions to trimethoprim/sulfamethoxazole occur with a high frequency in human immunodeficiency virus (HIV)-infected patients. This study tested whether differences in oxidative metabolism and plasma reductive capacity correlate with sulfonamide intolerance in patients with HIV. Eighteen stable outpatients with HIV were prospectively studied. Nine patients had documented histories of hypersensitivity reactions to trimethoprim/sulfamethoxazole and nine did not. Urinary caffeine metabolite ratios assessed the activity of two oxidative enzymatic pathways: cytochrome P-450 1A2 (demethylation) and 8-hydroxylation. Plasma cyst(e)ine was used as a measure of reductive capacity. The trimethoprim/sulfamethoxazole-intolerant group showed greater rates of 8-hydroxylation, lower rates of demethylation, and lower cyst(e)ine levels. The results of this pilot study extend previous observations of differences in oxidative metabolism and reductive capacity that exist within the population of HIV-infected individuals. In addition, these findings lay the groundwork for future interventional studies that could use agents to inhibit sulfonamide oxidation and increase reductive capacity in sulfonamide-intolerant patients with HIV when rechallenged with trimethoprim/sulfamethoxazole.
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PMID:Comparisons of oxidative metabolism and reductive capacity in sulfonamide-tolerant and -intolerant patients with human immunodeficiency virus. 901 72

Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.
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PMID:Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole. 914 45

Azole resistance in the pathogenic yeast Candida albicans is an emerging problem in the human immunodeficiency virus (HIV)-infected population. The target enzyme of the azole drugs is lanosterol 14alpha demethylase (Erg16p), a cytochrome P-450 enzyme in the biosynthetic pathway of ergosterol. Biochemical analysis demonstrates that Erg16p became less susceptible to fluconazole in isolate 13 in a series of isolates from an HIV-infected patient. PCR-single-strand conformation polymorphism (PCR-SSCP) analysis was used to scan for genomic alterations of ERG16 in the isolates that would cause this change in the enzyme in isolate 13. Alterations near the 3' end of the gene that were identified by PCR-SSCP were confirmed by DNA sequencing. A single amino acid substitution (R467K) that occurred in isolate 13 was identified in both alleles of ERG16. Allelic differences within the ERG16 gene, in the ERG16 promoter, and in the downstream THR1 gene were eliminated in isolate 13. The loss of allelic variation in this region of the genome is most likely the result of mitotic recombination or gene conversion. The R467K mutation and loss of allelic variation that occur in isolate 13 are likely responsible for the azole-resistant enzyme activity seen in this and subsequent isolates. The description of R467K represents the first point mutation to be identified within ERG16 of a clinical isolate of C. albicans that alters the fluconazole sensitivity of the enzyme.
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PMID:The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans. 921 Jun 71

Fluconazole, an inhibitor of certain human cytochrome P-450 isozymes, is used for the prevention and treatment of a broad range of fungal infections that predominantly affect immunocompromised individuals. This study evaluated the influence of fluconazole on the steady-state pharmacokinetics of delavirdine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, in 13 HIV-1-infected patients with CD4 counts ranging from 186 to 480/mm3. Both the control group (n = 5) and the fluconazole group (n = 8) received 300 mg of delavirdine mesylate every 8 h for 30 days; subjects in the fluconazole group took a 400-mg, once-daily dose of fluconazole on study days 16 to 30. Harvested plasma from serial blood samples collected on days 15, 16, and 30 were assayed for concentrations of delavirdine and its N-desalkyl metabolite by a reversed-phase high-pressure liquid chromatography (HPLC) method. Blood samples obtained on days 16 and 30 were also assayed for fluconazole by HPLC. Delavirdine mesylate alone and in combination with fluconazole was well tolerated. There were no significant differences (P > 0.16) in delavirdine pharmacokinetic parameters between treatment groups on day 15 or day 30. After coadministration of fluconazole and delavirdine mesylate for 2 weeks (day 30), no significant differences (P > 0.058) were observed in any delavirdine pharmacokinetic parameters relative to those after receiving delavirdine mesylate alone (day 15) after in the fluconazole group. Fluconazole pharmacokinetic parameters were similar to those previously reported for healthy volunteers and HIV-positive patients. On the basis of these findings, fluconazole and delavirdine mesylate may be taken concurrently without adjustment of the dose of either drug.
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PMID:Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. 930 80

KNI-272 is a tripeptide protease inhibitor for treating human immunodeficiency virus type 1 (HIV-1). In in vitro stability studies using rat tissue homogenates, KNI-272 concentrations in the liver, kidney, and brain decreased significantly with time. Moreover, in tissue distribution studies, KNI-272 distributed highly to the liver, kidney, and small intestine in vivo. From these results and reported physiological parameters such as the tissue volume and tissue blood flow rate, we considered the liver to be the main organ which takes part in the metabolic elimination of KNI-272. Then the hepatic metabolism of KNI-272 was more thoroughly investigated by using rat liver microsomes. KNI-272 was metabolized in the rat liver microsomes, and five metabolites were found. The initial metabolic rate constant (kmetabolism) tended to decrease when the KNI-272 concentration in microsomal suspensions increased. The calculated Michaelis-Menten constant (K(m)) and the maximum velocity of KNI-272 metabolism (Vmax), after correction for the unbound drug concentration, were 1.12 +/- 0.09 micrograms/ml (1.68 +/- 0.13 microM) and 0.372 +/- 0.008 microgram/mg of protein/min (0.558 +/- 0.012 nmol/mg of protein per min), respectively. The metabolic clearance (CLint,metabo), calculated as Vmax/K(m), was 0.332 ml/mg of protein per min. Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform. In addition, ketoconazole, a representative CYP3A inhibitor, inhibited KNI-272 metabolism competitively, and the inhibition constant (Ki) was 4.32 microM.
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PMID:Metabolic characterization of a tripeptide human immunodeficiency virus type 1 protease inhibitor, KNI-272, in rat liver microsomes. 1004 66

The discovery of human immunodeficiency virus (HIV) protease inhibitors is an example in which pharmacokinetic evaluation was implemented early in the discovery phase to obtain optimal pharmacological and pharmacokinetic properties. Currently, three HIV protease inhibitors, saquinavir, indinavir and ritonavir are clinically available. As a family, these HIV protease inhibitors are characterized pharmacologically by their ability to inhibit the viral protease enzyme. Pharmacokinetically, they are quite different due to their dissimilarity in physicochemical properties. Bioavailability appears to be limited with saquinavir, but not with indinavir and ritonavir. Although all three drugs are metabolized extensively by cytochrome P-450, saquinavir and indinavir are high clearance drugs while ritonavir is a low clearance drug. Despite their significant differences in elimination clearance, all three HIV proteases are given at high oral doses (600-800 mg) either twice or three times daily. These HIV protease inhibitors show superior therapeutic activity and a more favorable safety profile than those reported for the established reverse transcriptase inhibitors. However, the potential for interactions with other drugs metabolized by the CYP 3A4 isoform appears to be considerable. In addition, repeated administration of enzyme inducers results in a substantial decrease of plasma concentrations of protease inhibitors. Therefore, co-administration of drugs, such as rifampicin and rifabutin, must be avoided. HIV protease inhibitors are promising in the treatment of AIDS. Although they are not a cure, they can significantly inhibit that viral replication and improve the quality of life for people who have HIV infection.
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PMID:Human immunodeficiency virus protease inhibitors. From drug design to clinical studies. 1083 59

Superficial fungal infections or tinea infections (also known as the dermatophytoses) are commonly encountered conditions in clinical practice, affecting the skin, hair, and nails. The most commonly prescribed modality to treat these infections is topical antifungal therapy. However, this method of treating tinea infections may be less convenient and efficacious in the immunocompromised patient. In such patients, skin infections are more difficult to treat because the disease is often more extensive and severe. Tinea infections of the hair and nails usually require oral therapy. Further, topical treatment is not as efficacious as oral antifungal therapy and, with the exception of the topical antifungal agent ciclopirox, is not indicated for the treatment of tinea unguium (onychomycosis). The 2 most frequently prescribed oral antifungal agents to treat onychomycosis are itraconazole and terbinafine. In the general population, both agents are effective in treating fungal nail infections; however, differences in the agents' mechanism of action and metabolic pathways result in differences in efficacy and drug-drug interaction potential. However, limited data exist on the use of these agents in immunocompromised patients for the treatment of onychomycosis and superficial tinea infections. The available efficacy data we have are limited to case reports or small pilot studies; thus, data supporting the efficacy of these agents for the treatment of tinea infections in the immunocompromised patient must be extrapolated from the general population. For safety issues, however, some postmarketing data exist supporting the safety of these agents in the diabetic and human immunodeficiency virus (HIV) patients populations; indeed, both agents appear to be safe. However, one contrasting point between these 2 agents is drug interactions. Oral terbinafine, unlike itraconazole (a potent cytochrome P-450 [CYP] 3A4 inhibitor), has a relatively low potential for drug-drug interactions, making terbinafine a useful agent for the treatment of tinea infections in immunocompromised patients (e.g., those who are HIV positive and those with diabetes), who are likely to be receiving concomitant medications. Further, recently conducted studies of terbinafine for the treatment of tinea pedis, tinea cruris, and tinea corporis infections in these high-risk patient groups also support efficacy claims and reemphasize its relatively safe profile and low potential for drug interactions. Additional studies in other immunocompromised patient populations may be useful to confirm recent studies and expand the potential use for this agent.
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PMID:Role of oral antifungal agents for the treatment of superficial fungal infections in immunocompromised patients. 1149 33

A previously published report provided guidelines for managing the pharmacologic interactions that can result when patients receive protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection together with rifamycins for the treatment of tuberculosis (TB). Protease inhibitors and NNRTIs are antiretroviral agents that are substrates that may inhibit or induce cytochrome P-450 isoenzymes (CYP450). Rifamycins are antituberculosis agents that induce CYP450 and may decrease substantially blood levels of the antiretroviral drugs. The pharmacologic interactions are called "drug-drug" because, in addition to the effect rifamycins have on protease inhibitors and NNRTIs, the antiretroviral agents may affect the blood levels of rifamycins. This notice presents updated data pertaining to drug-drug interactions between these agents and recommendations for their use from a group of CDC scientists and outside expert consultants.
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PMID:Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. 1179


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