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 interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.
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PMID:Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. 1066 58

1. The in vitro metabolism of indinavir (CRIXIVAN, MK-0639, L-735,524), an HIV protease inhibitor, was evaluated using liver microsomes from cynomolgus monkey, rhesus monkey, chimpanzee and human. Indinavir exhibited marked species differences in metabolism. The overall rate of indinavir metabolism varied > 4-fold among primates (84 pmol/min/mg protein in cynomolgus monkey versus 20.4 pmol/min/mg protein in human) and followed the rank order: cynomolgus monkey > rhesus monkey > chimpanzee > human. 2. The cis-(indan)hydroxylated metabolite of indinavir was formed only in cynomolgus and rhesus monkey livers, whereas trans-(indan)hydroxylation and N-dealkylation were observed as the major metabolites in all primates tested. Inhibition studies with P450-selective inhibitors (ketoconazole, quinine, quinidine) and monoclonal antibodies (against CYP2D6 or CYP3A4) indicated that a cytochrome P450 isoform of the CYP2D subfamily is involved in the formation of the unique cis-(indan) hydroxylated metabolite in monkey, whereas all other oxidative metabolites, including the trans-(indan)hydroxylated metabolite, are formed by CYP3A isoform(s). 3. The present study has demonstrated that monkeys were unique in their abilities to form the stereoselective metabolite and were not appropriate surrogates for the qualitative prediction of indinavir metabolism in human.
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PMID:Comparative in vitro metabolism of indinavir in primates--a unique stereoselective hydroxylation in monkey. 1071 20

L-754,394, a furanopyridine derivative, is an experimental HIV protease inhibitor. Previous studies from this laboratory have demonstrated that L-754,394 is cleared very rapidly in animals, and that this drug is a potent mechanism-based inactivator (suicide inhibitor) for CYP3A4 in human liver microsomes. Because L-754,394 is a high-clearance drug and an enzyme inactivator, it is expected that this drug will be subject to significant first-pass metabolism, and that the degree of enzyme inactivation will be dependent not only on the dose, but also on the route of administration. The purpose of this study is to examine the effects of dose and route of administration on the kinetics of L-754,394 using rats and dogs as animal models. In both rats and dogs, L-754,394 exhibited marked dose-dependent pharmacokinetics after i.v. and oral administration. Irrespective of i.v. or oral administration, the area under the plasma concentration-time curve from zero to infinity increased with dose in a greater than proportional manner. However, the magnitude of area under the plasma concentration-time curve from zero to infinity increase was much greater after oral dosing than after i.v. administration, indicating route-dependent pharmacokinetics. Data from in vitro and in vivo studies suggested that the dose- and route-dependent pharmacokinetics were due mainly to the inactivation (destruction) of the enzymes responsible for its own metabolism.
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PMID:Route-dependent nonlinear pharmacokinetics of a novel HIV protease inhibitor: involvement of enzyme inactivation. 1072 15

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.
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PMID:Potential interaction between ritonavir and carbamazepine. 1090 77

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.
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PMID:Drug interactions with cisapride: clinical implications. 1092 50

Assessing the activity of CYP3A4 is important for predicting the pharmacokinetic behavior of protease inhibitors in HIV positive patients, especially in pregnant women. The endogenous hormonal ratio of 6beta-hydroxycortisol (beta-OHF) to cortisol (F) in the urine is an index for metabolic enzyme activity of cytochrome p-450 (CYP) 3A4. Because the ratio is a unique way to assess the enzyme activity without using any exogenous probes for this isozyme, it is practical for use in pregnant women. In this paper, we describe a method using high performance liquid chromatography (HPLC) for 6beta-OHF in urine from pregnant women to estimate the ratio of 6beta-OHF/F. Urinary 6beta-OHF was measured by using C18-cartridge solid phase extraction and isocratic HPLC. Aliquots (1 ml) of urine samples spiked with internal standard, 6beta-hydroxyprednisolone (6beta-OHPSL), were alkalinized with NaOH, then applied to C18-cartridges, which were washed with water and hexane and eluted with ethyl acetate. After the effluents were dried and reconstituted in 10% acetonitrile, the samples were analyzed by HPLC using an isocratic mobile phase (acetic acid/acetonitrile/50 mM potassium dihydrogenphosphate: 0.2/9/90.8; v/v) and ultraviolet detection at 245 nm. The recoveries of 6beta-OHF from C18 cartridges were 93.2 and 93.9% when the authentic 6beta-OHF was added to the urine sample at the concentration of 50 and 300 ng/ml, respectively. Intra- and inter-day variations estimated at concentrations of 113-674 ng/ml were 2.9-5.6 and 4.9-8.1%, respectively. The method was applied to morning urine samples collected from HIV-positive pregnant women managed with protease inhibitor containing anti-retroviral regimens.
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PMID:Liquid chromatographic determination of urinary 6beta-hydroxycortisol to assess cytochrome p-450 3A activity in HIV positive pregnant women. 1097 39

Neurologic manifestations of HIV infection are quite diverse and can develop into seizures. Because new drug therapies have been developed, it is important to know the interactions between antiretroviral and antiepileptic agents. A 36-year-old patient with HIV developed a set of progressive left hemiparesis and secondarily generalized partial seizures related to progressive multifocal leukoencephalopathy. Phenytoin and carbamazepine were necessary to control the seizures. Instead of diverse antiretroviral therapies, the viral load was increased. Protease inhibitors (ritonavir and saquinavir) were added to the treatment and the patient developed progressive ataxia related to carbamazepine toxicity. Carbamazepine was discontinued and the patient remained asymptomatic. The patient was diagnosed with carbamazepine toxicity related to the introduction of ritonavir. Ritonavir is a potent inhibitor of hepatic cytochrome P450, mainly the CYP3A4 isoform. Carbamazepine is metabolized by this subsystem. Ritonavir acted as a CYP3A4 inhibitor, diminishing carbamazepine metabolism and provoking an increase in serum levels and clinical toxicity. We present a case of interaction between ritonavir and carbamazepine. Interaction between antiepileptic and antiretroviral agents is an emergent problem caused by the increasing association of the two therapies. We recommend strict monitoring of serum antiepileptic drug (AED) levels to avoid toxicity and inadequate seizure control.
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PMID:Protease inhibitor-induced carbamazepine toxicity. 1102 Jan 27

Improving outcomes for patients with depression involves selecting the best possible drug therapy. Considerations relevant to drug product selection include: 1) pharmacokinetic issues such as half-life and time to steady-state, and protein binding; 2) pharmacodynamic drug-drug interactions; and 3) drug metabolism-related drug interactions. A comparison of selected antidepressants with an emphasis on venlafaxine's similarities and differences is presented. Based on these parameters, selecting an antidepressant medication, such as venlafaxine, that has a low potential for drug interactions at the Cytochrome P450 (CYP) enzyme system, and is easy to monitor and dose, facilitate successful treatment of patients. Venlafaxine has been evaluated in clinical studies that demonstrate low to negligible drug interaction potential at CYP2D6, CYP1A2, CYP2C19, and CYP3A4. Its short half-life and time to steady-state, when coupled with the extended release characteristics of the preferred dosage formulation allow for once daily dosing and rapid attainment of therapeutic effects. The CYP3A4 system is involved in both first-pass metabolism and systemic clearance of medications. Drug interactions at this isoenzyme have proven to be of high clinical relevance ranging from cardiovascular toxicity and death with commonly used drugs such as cisapride, to subtherapeutic levels of cyclosporine or protease inhibitors leading to transplant rejection or HIV relapse. Reasons for the under detection and reporting of drug interaction mediated adverse events include healthcare system structure, the poor return to follow up of non-adherent patients, the need for greater education and training of clinicians to recognize drug-related adverse events, and the reluctance of patients to spontaneously communicate about the unpleasant effects of their medication.
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PMID:Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: focus on venlafaxine. 1109 12

Delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is metabolized primarily through desalkylation catalyzed by CYP3A4 and CYP2D6 and by pyridine hydroxylation catalyzed by CYP3A4. It is also an irreversible inhibitor of CYP3A4. The interaction of delavirdine with CYP2C9 was examined with pooled human liver microsomes using diclofenac 4'-hydroxylation as a reporter of CYP2C9 catalytic activity. As delavirdine concentration was increased from 0 to 100 microM, the K(M) for diclofenac metabolism rose from 4.5+/-0.5 to 21+/-6 microM, and V(max) declined from 4.2+/-0.1 to 0.54+/-0.08 nmol/min/mg of protein, characteristic of mixed-type inhibition. Nonlinear regression analysis revealed an apparent K(i) of 2.6+/-0.4 microM. There was no evidence for bioactivation as prerequisite to inhibition of CYP2C9. Desalkyl delavirdine, the major circulating metabolite of delavirdine, had no apparent effect on microsomal CYP2C9 activity at concentrations up to 20 microM. Several analogs of delavirdine showed similar inhibition of CYP2C9. Delavirdine significantly inhibited cDNA-expressed CYP2C19-catalyzed (S)-mephenytoin 4'-hydroxylation in a noncompetitive manner, with an apparent K(i) of 24+/-3 microM. Delavirdine at concentrations up to 100 microM did not inhibit the activity of CYP1A2 or -2E1. Delavirdine competitively inhibited recombinant CYP2D6 activity with a K(i) of 12.8+/-1.8 microM, similar to the observed K(M) for delavirdine desalkylation. These results, along with previously reported experiments, indicate that delavirdine can partially inhibit CYP2C9, -2C19, -2D6, and -3A4, although the degree of inhibition in vivo would be subject to a variety of additional factors.
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PMID:Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6. 1112 28

Amprenavir is a novel protease inhibitor with antiviral activity, and was approved in the U.S. (AGEN-ERASE) in 1999 for use in combination with other antiretrovirals for the treatment of HIV infection. The drug is developed by Kissei Pharmaceuticals Co., Ltd. in Japan, approved in the same year, and has been distributed by them (PROZEI). Amprenavir achieves a viral load of less than 400 copies/ml when it is given in triple combination therapy in both therapy-naive patients and patients previously treated with nucleoside reverse transcriptase inhibitors (NRTI). The recommended dose of amprenavir is eight 150-mg capsules, twice daily, or 1200 mg, b.i.d. Amprenavir may be taken with or without a meal; however, it should not to be taken with high-fat meals because its oral bioavailability may possibly be affected by fat. One of the major concerns associated with anti-HIV agents is the resistance mutation development, and the presence of I50V, M46I/L, I47V, I54L/V and I84V genotype has been observed in amprenavir therapy experienced subjects. Differences in resistance patterns and resistance mutation interactions may have amprenavir recognized as an alternative choice of drugs in maintaining efficacy. Therefore, amprenavir is believed to add an important treatment option in HIV infection therapy. It should be noted that P450 isozyme CYP3A4 is responsible for amprenavir; thus, care must be taken to avoid combined amprenavir with drugs that affect the action of CYP3A4, that act on the production CYP3A4 substrates, or that are metabolized by CYP3A4 metabolism. Amprenavir is the fifth protease inhibitor approved in Japan, and it is important to understand its differential and identical properties from other protease inhibitors to maximize its efficacy.
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PMID:[Pharmacological study and clinical effect of HIV protease inhibitor amprenavir]. 1123 98


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