A review of the pharmacokinetics of zidovudine in man

Cload, P.

doi:10.1016/s0163-4453(89)80076-3

Cited by 33 publications

(24 citation statements)

References 5 publications

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“…AZT has become the first-line treatment for patients with HIV infection (McLeod & Hammer, 1992;Cooper et al, 1993) and is an important part of the new 'rotating' therapeutic regimes for HIY. In well individuals AZT is efficiently absorbed after oral administration with 60% bioavailability (Cload, 1988). The drug reaches peak serum concentrations within 30 to 60 min after ingestion and has a half-life of about 1 h (Laskin et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Intra-Individual Variation in Serum AZT Concentration is Not Related to Intestinal Absorption or Small Intestinal Inflammatory Changes in Human Immunodeficiency Virus-Infected Subjects

Sherwood

Marsden

Stein

et al. 1997

Antivir Chem Chemother

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3′-Azido-3′-deoxythymidine (AZT; zidovudine) either alone or in combination with didanosine or another nucleoside analogue is the first-line treatment for patients with human immunodeficiency virus (HIV) infection, many of whom have concurrent gastrointestinal (GI) disease. This study assessed whether the absorption of AZT was affected by GI disease. The absorption and pharmacokinetics of AZT in 23 HIV-infected individuals was measured after a single dose of AZT and was related in 12 patients to small intestinal function. Levels of AZT and its metabolite 5′-glucopyranuronosylthymidine (G-AZT) were measured by radioimmunoassay. Intestinal permeability was assessed by differential urinary excretion of orally administered lactulose/1-rhamnose; absorptive capacity was measured simultaneously by the urinary excretion of 3-o-methyl-D-glucose, d-xylose and 1-rhamnose. Small intestinal inflammation was assessed by faecal excretion of indium-labelled neutrophils. Peak levels of AZT in serum varied between 170 and 1820 ng mL−1. The metabolite G-AZT was present in serum at peak concentrations varying from 1020 to 9930 ng mL−1. There was up to a sevenfold variation in the area under the curve (AUC). The time to maximum serum concentration for AZT was between 30 and 120 min, with an absorption half-life of between 2 and 38 min. The median elimination half-life was 57 min (range 46–72 min), close to the predicted half-life of 60 min. Intestinal permeability was increased in six of the 12 subjects studied and eight had evidence of reduced absorptive capacity. Ten of the 12 patients had evidence of small intestinal inflammation. We concluded that neither changes in permeability nor absorptive capacity influenced the absorption of AZT. There was no relationship between the presence of intestinal inflammation and AZT absorption. This study showed a significant intra-individual variation of serum AZT levels which cannot be explained on the basis of altered intestinal absorptive capacity or intestinal inflammatory changes.

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Section: Discussionmentioning

confidence: 99%

Intra-Individual Variation in Serum AZT Concentration is Not Related to Intestinal Absorption or Small Intestinal Inflammatory Changes in Human Immunodeficiency Virus-Infected Subjects

Sherwood

Marsden

Stein

et al. 1997

Antivir Chem Chemother

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“…As per convention in the antimicrobial resistance field, concentrations were plotted in micrograms per milliliter. IC 50 and IC 90 values were calculated using regression analysis. The MIC values in the same experiments were determined according to the CLSI guidelines for microbroth dilution, that is, the lowest concentration of compound resulting in complete visible inhibition of growth.…”

Section: Dose-response Curvesmentioning

confidence: 99%

“…However, 14 (25%) compounds initially identified as direct antimicrobials displayed lower MIC or IC 50 values in the presence of meropenem and were therefore reclassified as adjunctive. Compounds for which an MIC or IC 50 could not be observed and showing less than 25% inhibition at concentrations equal to those tested in the HTS (50.7% of all compounds tested) were classified as negative.…”

Section: Secondary Analyses and Two-dimensional Synergy Testingmentioning

confidence: 99%

“…In contrast, DPI exhibited a more gradual inhibition. AZT, a nucleoside analog used to treat human immunodeficiency virus infection, 27 showed a sigmoidal inhibition curve, with appreciable inhibition at concentrations well below its MIC (4 mg mL IC 50 20-fold below the MIC. Spectinomycin, an aminoglycoside antibiotic used to treat Neisseria gonorrhoeae infections, 28 was also selected for further analysis (Fig.…”

Section: Generation Of Dose-response Curvesmentioning

confidence: 99%

“…Specifically, in phase I dose escalation trials, intravenous administration of 7.5 mg kg -1 every 4 h was associated with a 4.7 mg mL -1 peak serum concentration. 50 Overall, these observations suggest that AZT may be a therapeutic adjunct for CRE worthy of further experimental investigation. Of note, AZT did not appear to act synergistically with meropenem (FIC >0.5, data not shown).…”

mentioning

confidence: 93%

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Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Smith

Kirby

2016

ASSAY and Drug Development Technologies

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We describe development and validation of a high-throughput screen (HTS) for identifying small molecules that restore the efficacy of carbapenems (adjunctives) and/or directly inhibit growth of carbapenem-resistant Enterobacteriaceae (CRE). Our HTS assay is based on a screen-counterscreen approach using a representative multidrug-resistant CRE strain, Klebsiella pneumoniae BIDMC12A. Specifically, we tested the ability of small molecules to inhibit bacterial growth in the presence (screen) or absence (counterscreen) of meropenem, a representative carbapenem antibiotic. Primary screening of 11,698 known bioactive compounds identified 14 with adjunctive activity and 79 with direct antimicrobial effect. Secondary screening identified triclosan as a strongly synergistic meropenem adjunctive (fractional inhibitory concentration = 0.48) and confirmed azidothymidine (AZT) (minimal inhibitory concentration [MIC] = 4 lg mL ) as potent direct antimicrobials. Spectrum of activity of AZT and spectinomycin was tested against a collection of 103 representative Enterobacteriaceae strains (&50% CRE). AZT, a nucleoside analog used to treat human immunodeficiency virus, demonstrated an MIC 50 of 2 lg mL -1 . Spectinomycin, an antibiotic used to treat gonorrhea, had an MIC 50 of 32 lg mL -1 . Therefore, a significant percentage of CRE strains appeared relatively susceptible to these antimicrobials. These data identified AZT and spectinomycin as available agents warranting further study for potential treatment of multidrug-resistant CRE infection. Our results provide proof of principle and impetus for performing a largescale HTS for discovery of novel, small-molecule adjunctives and antibacterial agents directly targeting CRE.

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Zidovudine and Other Reverse Transcriptase Inhibitors in the Management of Human Immunodeficiency Virus‐Related Disease

Matthews,

Cersosimo,

Spivack

1991

Pharmacotherapy

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Licensed in 1987, zidovudine remains the only medication with proved efficacy for the treatment of disease caused by the human immunodeficiency virus (HIV). New information on the pharmacology (adults and children), effects of kidney and liver dysfunction on the disposition of the drug, and drug‐drug interactions have improved the way we use and monitor this agent. The serious toxicity associated with zidovudine has led researchers to develop safer dosage regimens. Also, recognition that zidovudine slows but does not halt progression of disease has increased the search for effective alternatives. The best‐studied agents are didanosine (2′, 3′‐dideoxyinosine, ddI), zalcitabine (2′,3′‐dideoxycytidine, ddC), and foscarnet.

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A review of the pharmacokinetics of zidovudine in man

Cited by 33 publications

References 5 publications

Intra-Individual Variation in Serum AZT Concentration is Not Related to Intestinal Absorption or Small Intestinal Inflammatory Changes in Human Immunodeficiency Virus-Infected Subjects

Intra-Individual Variation in Serum AZT Concentration is Not Related to Intestinal Absorption or Small Intestinal Inflammatory Changes in Human Immunodeficiency Virus-Infected Subjects

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Zidovudine and Other Reverse Transcriptase Inhibitors in the Management of Human Immunodeficiency Virus‐Related Disease

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