Pharmacokinetics of zidovudine (azidothymidine). III. Effect of pregnancy.

Administration of zidovudine (ZDV or azidothymidine) to pregnant women with HIV infection may be of benefit to both the mother and her unborn child. Since pregnancy can have a substantial effect on the pharmacokinetics of a drug, the effect of pregnancy on the pharmacokinetics of ZDV (10 mg/kg, i.v. bolus) was studied in the macaque (Macaca nemestrina). The plasma clearance, steady-state volume of distribution, and terminal half-life of ZDV were found not to be significantly affected by pregnancy. Based on these findings, we predict that the pharmacokinetics of ZDV in women will not be affected by pregnancy. If this prediction is found to be correct, the dose of ZDV need not be adjusted when the drug is administered to pregnant women.

Simple and effective procedure for complete urine collection from infant macaques (Macaca nemestrina).

A diaper method, used in pediatric medicine, has been adapted and validated for total urine collection from infant macaques (Macaca nemestrina). The device consists of cellulose sponges and polyethylene sheets. The method proposed is non-invasive, simple, and does not significantly hinder the movement of the infant. The method should be useful when one is conducting pharmacokinetic studies in which total urine collection is required.

Pharmacokinetics of zidovudine (azidothymidine). I. Transplacental transfer.

Administration of zidovudine (ZDV) to pregnant women with human immunodeficiency virus infection may be of benefit to both the mother and the unborn child. Before testing this hypothesis, however, it is necessary to determine the transplacental transfer, fetal toxicity, and fetal accumulation of ZDV (if any) in a representative animal model. Therefore, the transplacental transfer and the fetal accumulation of ZDV were determined at steady state in near-term pregnant macaques (Macaca nemestrina). ZDV was administered to five dams at a rate predicted to produce a steady-state plasma concentration of about 1 microgram/ml. When steady state was predicted to have been achieved, a cesarean section was performed on each dam. At this time, blood samples from the dam (peripheral vein) and the fetus (umbilical vein) were obtained simultaneously. The plasma concentration of ZDV and its major metabolite, zidovudine glucuronide (ZDVG), were determined by a specific high-performance liquid chromatography (HPLC) method. The ratio of steady-state plasma concentration (Crss) of ZDV in the fetus (Cssf) to that in the dam (Cssd) (Crss = Cssf/Cssd) was found to be close to unity (0.826 +/- 0.067). Similar results were obtained for the ratio of steady-state unbound ZDV plasma concentration (0.852 +/- 0.083). We conclude that ZDV readily crosses the placenta, probably by passive diffusion, and that ZDV does not accumulate in the fetus when administered to near-term pregnant macaques.

Pharmacokinetics of zidovudine (azidothymidine). II. Development of metabolic and renal clearance pathways in the neonate.

The pharmacokinetics of zidovudine (ZDV or azidothymidine) were investigated in newborn macaques (Macaca nemestrina) at various ages ranging from less than 1 week to 4 months. The mean ZDV total plasma clearance, renal clearance, and the metabolic clearance of ZDV to the glucuronide (ZDVG) were significantly (p less than 0.05) smaller during the first week of life (6.15 +/- 1.03, 4.25 +/- 0.36, and 1.19 +/- 0.67 ml/min/kg, respectively) than the corresponding estimates at the age of 4 months (19.62 +/- 3.5, 8.28 +/- 1.90, and 8.28 +/- 2.24 ml/min/kg, respectively). The mean estimates of these parameters at 4 months were close to those found in adult macaques (23.55 +/- 1.48, 10.05 +/- 0.75, and 10.5 +/- 1.9 ml/min/kg, respectively), indicating that these clearance pathways develop rapidly, within 4 months of birth. If similar results are obtained in human neonates, therapeutic drug monitoring should be instituted when administering ZDV to this population so that the dose of ZDV may be adjusted to correspond with age-related changes in total plasma clearance of ZDV.

Supplementation of total parenteral nutrition solutions with ferrous citrate.

Daily infusion of a total parenteral nutrition (TPN) formulation containing 1 liter of 5.5% Travasol provides less than 0.1 milligrams of iron. By comparison, a formulation which includes a liter of 10% Travamin provides 2 milligrams of iron per day. To meet iron requirements in patients infusing formulations containing Travasol, iron was added as ferrous citrate. In in virto experiments, 74% of this iron was available to transferrin. In seven patients in whom in vivo availability was tested by red cell incorporation, the mean availability was 81%. Ferrous citrate is recommended as a safe, effective additive to TPN solutions for adult patients requiring iron supplements.