Pharmacokinetic Drug Interactions with Antimicrobial Agents

Gillum, J G; Israel, Debra S.; Polk, Ron E.

doi:10.2165/00003088-199325060-00005

Cited by 130 publications

(62 citation statements)

References 231 publications

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“…Since the pharmacokinetics of ddI in dogs are similar to those from limited observations in humans, similarities in metabolic profiles of these two species (i.e., xanthine oxidase) may explain the lack of interaction found in this trial (see below). Like other azoles, fluconazole is an inhibitor of multiple hepatic P-450 enzymes; it also appears to inhibit some non-P-450 enzymes, such as uridine diphosphate-glucurosyl transferase, which is responsible for the metabolism of ZDV (6,9,19). However, we found that the pharmacokinetics of ddI are not altered by fluconazole when both are given at commonly prescribed dosages.…”

Section: Discussionmentioning

confidence: 57%

“…Fluconazole is well absorbed in the HIV population and is frequently prescribed for prophylaxis and treatment of fungal infections (6). However, fluconazole inhibits a number of hepatic P-450 enzymes that are responsible for the metabolism of many drugs, such as theophylline, phenytoin, cyclosporin, and rifabutin (9,16,21). In addition, fluconazole has recently been shown to decrease clearance of zidovudine (ZDV), a drug which is metabolized primarily by glucuronidation (19).…”

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confidence: 99%

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Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

Bruzzese

Gillum

Israel

et al. 1995

Antimicrob Agents Chemother

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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 ng ⅐ hr/ml) and following fluconazole treatment (1,486 ؎ 649 ng ⅐ 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.Patients infected with human immunodeficiency virus (HIV) are commonly treated with multiple medications concurrently. Fluconazole is well absorbed in the HIV population and is frequently prescribed for prophylaxis and treatment of fungal infections (6). However, fluconazole inhibits a number of hepatic P-450 enzymes that are responsible for the metabolism of many drugs, such as theophylline, phenytoin, cyclosporin, and rifabutin (9,16,21). In addition, fluconazole has recently been shown to decrease clearance of zidovudine (ZDV), a drug which is metabolized primarily by glucuronidation (19). The mechanism for this latter interaction is unknown, but it demonstrates that the full spectrum of metabolic enzymes which are inhibited by fluconazole remains unknown.The antiretroviral agent 2Ј,3Ј-dideoxyinosine (didanosine or ddI) is used to treat persons infected with HIV (1, 10). Approximately 50 to 70% of the absorbed dose of ddI appears in urine as various metabolites, although the full metabolic profile is unknown (3a, 11a, 14). Dose-related toxicities of ddI include peripheral neuropathy and pancreatitis (5,15,22). Since fluconazole and ddI are commonly coadministered, fluconazole has the potential to inhibit the metabo...

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Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 99%

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

Bruzzese

Gillum

Israel

et al. 1995

Antimicrob Agents Chemother

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“…In addition, RIF-mediated induction of CYP3A enzyme activity occurred in a concentration-dependent fashion up to 30 µM, but at a higher concentration (100 µM), the increased activity was reduced. These phenomena can be attributed to the biochemical properties of RIF; it has the ability not only to induce CYP3A subfamily enzymes 35) but also to inhibit the activities of several CYP enzymes, including CYP3A4. 36) CALUX in HPL-A3 was further increased not only by hPXR-selective activators (RIF and CLO) but also by human/ mouse/rat PXR activators (TAM and NIC), while no such significant increases by mouse/rat PXR activators (DEX and PCN) were observed.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Stable Human Cell Line, HPL-A3, for Use in Reporter Gene Assays of Cytochrome P450 3A Inducers

Sekimoto

Sano

Hosaka

et al. 2012

Biological & Pharmaceutical Bulletin

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We have established a stable human cell line, termed HPL-A3, by co-transfection of a human pregnane X receptor (hPXR) expression vector and a reporter plasmid (p3A4-hPXRE-Luc) containing a luciferase gene and a promoter/enhancer region of the human cytochrome P450 3A4 (CYP3A4) gene into a human hepatomaderived cell line, HepG2. We then examined the usefulness of HPL-A3 for a chemically activated luciferase expression (CALUX) assay of human CYP3A inducers. The induction of CALUX in HPL-A3 by hPXR activators, including rifampicin, occurred in time-and concentration-dependent fashions, whereas no such induction was observed using rat/mouse PXR activators, such as pregnenolone-16α-carbonitrile and dexamethasone. The hPXR activator-mediated induction of CYP3As, especially CYP3A4, was observed at levels of both mRNA and enzyme activity.

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“…However, CYP3A4 inducers such as rifampicin and rifabutin can reduce plasma concentrations of certain drugs up to 40-fold, effectively abolishing their efficacy (Gillum et al, 1993;Grange et al, 1994). For example, enhanced metabolism, produced by rifampicin, of the CYP3A substrate cyclosporine has resulted in organ graft rejections (Lucey et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

High Volume Bioassays to Assess Cyp3a4-Mediated Drug Interactions: Induction and Inhibition in a Single Cell Line

Yueh¹,

Kawahara²,

Raucy³

2004

Drug Metab Dispos

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ABSTRACT:Exposure to certain xenochemicals can alter the catalytic activity of the major drug-metabolizing enzyme, CYP3A4, either by enhancing expression of this cytochrome P450 or inhibiting its activity. Such alterations can result in adverse consequences stemming from drug-drug interactions. A simplified and reliable tool for detecting the ability of candidate drugs to alter CYP3A4 levels or inhibit catalytic activity was developed by stable integration of human pregnane X receptor and a luciferase vector harboring the CYP3A4 enhancers. Treatment of stable transformants, namely DPX-2, with various concentrations of inducers including rifampicin, mifepristone, troglitazone, methoxychlor, and kava produced dose-dependent increases in luciferase expression (between 2-and 40-fold above dimethyl sulfoxide-treated cells). Northern blot analyses of CYP3A4 mRNA in DPX-2 cells exhibited a good correlation to results generated with the reporter gene assay (r 2 ‫؍‬ 0.5, Drug interactions frequently occur when one drug modulates the metabolism of a second drug by inhibition or induction of a specific P450 enzyme. Given that CYP3A4 is the most abundant hepatic P450 enzyme and is responsible for the metabolism of a large number of currently used therapeutic agents, a major focus in determining the causes of drug interactions centers around identification of xenochemicals that alter the expression of CYP3A4 (Watkins, 1994). At least five categories of agents are considered CYP3A inducers: steroid hormones having either glucocorticoid or anti-glucocorticoid activities; phenobarbital and phenobarbital-like agents, such as polychlorinated biphenyls and organochlorine pesticides; macrolide antibiotics, including rifampicin; imidazole antifungal agents, such as clotrimazole; and receptor and enzyme antagonists, including nifedipine, troglitazone, and lovastatin (reviewed in Quattrochi and Guzelian, 2001).CYP3A4 induction is frequently considered clinically less important than inhibition of its catalytic activity because induction is expected to reduce the efficacy, rather than cause toxicity, of coadministered CYP3A substrates. However, CYP3A4 inducers such as rifampicin and rifabutin can reduce plasma concentrations of certain drugs up to 40-fold, effectively abolishing their efficacy (Gillum et al., 1993;Grange et al., 1994). For example, enhanced metabolism, produced by rifampicin, of the CYP3A substrate cyclosporine has resulted in organ graft rejections (Lucey et al., 1990). Rifampicin and the widely used herbal antidepressant St. John's wort also attenuate the efficacy of HIV protease inhibitors (Cvetkovic and Goa, 2003), hindering AIDS therapy. Along similar lines, enhanced metabolism of antitumor agents can diminish the progress of chemotherapy. In epilepsy patients, CYP3A4 induction by carbamazepine and phenytoin results in low plasma concentrations of midazolam, reducing the hypnotic effect (Backman et al., 1996). Moreover, rifampicin treatment results in diminished hypnosis associated with another agent, triazolam, wh...

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Pharmacokinetic Drug Interactions with Antimicrobial Agents

Cited by 130 publications

References 231 publications

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

Establishment of a Stable Human Cell Line, HPL-A3, for Use in Reporter Gene Assays of Cytochrome P450 3A Inducers

High Volume Bioassays to Assess Cyp3a4-Mediated Drug Interactions: Induction and Inhibition in a Single Cell Line

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