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

Abstract

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.

Zidovudine

“…[76] As seen in adults, the major route of elimination of zidovudine in children is by metabolism to GZDV. [77] In agreement with studies in adults, [78] limited data show that intestinal dysfunction in children with symptomatic HIV infection is not associated with reduced zidovudine intestinal absorption; [79] however, in patients with diarrhea zidovudine plasma concentrations may be reduced. [77] In agreement with studies in adults, [78] limited data show that intestinal dysfunction in children with symptomatic HIV infection is not associated with reduced zidovudine intestinal absorption; [79] however, in patients with diarrhea zidovudine plasma concentrations may be reduced.…”

Modern approach for determination of lactulose, mannitol and sucrose in human urine using HPLC–MS/MS for the studies of intestinal and upper digestive tract permeability

“…With this method, it is possible to detect common saccharides in extracts from plants [27]. Several HPLC procedures are available for the determination of sugars in urine [10,12,16,[28][29][30]. Some methods are based on refractive index detection [28], which has the advantage of being universal.…”

“…It is crucial to monitor and estimate the permeability of small intestine due to its relation with diseases like: coeliac disease [4,5], Leśniowski-Crohn disease [6], allergy for proteins in cow's milk [7], cirrhosis [8], HIV infection [9,10], chronic and acute diarrhea [11], pediatric intestinal diseases [12], cystic fibrosis [13] and damages caused by non-steroidal anti-inflammatory drugs [14].…”

Genetic Variation of Human UDP-Glucuronosyltransferase

“…The four constant exons are spliced to a single variable exon to produce a mature mRNA and a functional protein (see figure 4b) [reproduced from Pacifici and Pelkonen, [16] with permission from the publishers, Taylor & Francis]. [35] The ratio of urinary concentration of glucuronides of benzo(a) pyrene 7,10/8,9 tetrol to 1-hydroxy pyrene was shown to vary 6000-fold in patients with coal tar-treated psoriasis. [34] Zidovudine glucuronide peak levels in serum varied 7-fold in a patient population.…”