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Impaired absorption of zidovudine in patients with AIDS-related small intestinal disease
M S Kapembwa1, S C Fleming, M Orr
1Department of Genitourinary Medicine, Imperial College of Science, St Mary's Hospital Medical School, London, UK.
Objectives:
To investigate the effect of small intestinal disease (SID) on the absorption of zidovudine (ZDV) in patients with AIDS.
Methods:
Fourteen fasted homosexual men with AIDS received a single oral dose of ZDV (5 mg/kg). Nine subjects had clinical evidence of intestinal disease (chronic diarrhoea with wasting) confirmed by reduced fat absorption measured indirectly using the 14C-triolein test. Five subjects had AIDS-related symptoms other than those affecting the gastrointestinal tract with normal fat absorption. Sequential measurements of plasma ZDV including its glucuronide metabolite (GZDV) were obtained using radio-immunoassay and ZDV/GZDV concentrations-time profiles of both groups of subjects were compared. Comparisons were also made for each of the following computed variables: the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-6 h), the elimination half-life (t 1/2), and apparent oral clearance (CL0).
Results:
In patients with SID, Cmax ZDV was reduced (6.39 +/- 3.39 versus 11.51 +/- 5.01 mumol/l; P < 0.05) and Tmax ZDV prolonged (0.81 +/- 0.51 versus 0.40 +/- 0.14 h; P < 0.05) but AUC0-6 h ZDV was no different from the non-SID group (8.03 +/- 2.73 versus 14.56 +/- 9.0 mumol/l-1xh; P = 0.06). There were no differences in t 1/2 ZDV (1.22 +/- 0.20 versus 1.13 +/- 0.30 h) or CL0 ZDV (3017 +/- 1158 versus 1700 +/- 889 ml/min; P > 0.05) between SID and non-SID groups, respectively, and GZDV values were comparable between the two groups.
Conclusions:
These data suggest delayed absorption rather than altered metabolism of ZDV in AIDS-related SID and raise the possibility of drug malabsorption. The clinical efficacy of orally administered low-dose ZDV regimens may require further evaluation in patients with chronic diarrhoea and AIDS.
Insights
Small intestinal disease in patients with AIDS may delay zidovudine (ZDV) absorption, not alter its metabolism. This finding suggests potential malabsorption issues impacting oral ZDV efficacy in AIDS patients with chronic diarrhea.
Area of Science:
- Pharmacokinetics
- Gastroenterology
- Infectious Diseases
Background:
- Zidovudine (ZDV) is a crucial antiretroviral medication for managing HIV/AIDS.
- Small intestinal disease (SID) is a common complication in patients with AIDS, potentially affecting drug absorption.
- Understanding ZDV absorption in the context of SID is vital for optimizing treatment efficacy.
Purpose of the Study:
- To investigate the impact of small intestinal disease (SID) on the oral absorption of zidovudine (ZDV) in patients diagnosed with AIDS.
- To compare ZDV pharmacokinetics in AIDS patients with and without evidence of SID.
Main Methods:
- Oral zidovudine (ZDV) absorption was assessed in 14 fasted male AIDS patients.
- Nine patients had SID (chronic diarrhea, wasting, reduced fat absorption); five had AIDS without gastrointestinal symptoms and normal fat absorption.
- Plasma ZDV and its metabolite (GZDV) concentrations were measured over time, analyzing key pharmacokinetic parameters (Cmax, Tmax, AUC0-6 h, t 1/2, CL0).
Main Results:
- Patients with SID exhibited a reduced maximum plasma concentration (Cmax) and a prolonged time to reach Cmax (Tmax) for ZDV.
- No significant differences were observed in the area under the plasma concentration-time curve (AUC0-6 h), elimination half-life (t 1/2), or apparent oral clearance (CL0) between groups.
- Plasma concentrations of the ZDV glucuronide metabolite (GZDV) were comparable in both patient groups.
Conclusions:
- The findings suggest that SID primarily delays ZDV absorption rather than altering its metabolic pathways in AIDS patients.
- The results raise concerns about potential drug malabsorption in AIDS patients with SID.
- Further research is warranted to evaluate the clinical effectiveness of low-dose oral ZDV regimens in AIDS patients experiencing chronic diarrhea.