Efflux of zidovudine and 2',3'-dideoxyinosine out of the cerebrospinal fluid when administered alone and in combination to Macaca nemestrina.

To determine if there is active efflux of zidovudine (ZDV) and 2',3'-dideoxyinosine (ddI) out of the cerebrospinal fluid (CSF), and if this efflux is saturable, we investigated the steady-state CSF/plasma concentration ratio of the two drugs when administered alone or in combination. Constant-rate infusions of ZDV, ddI or both were administered to seven macaques (Macaca nemestrina) through a chronic venous catheter for a minimum of 28 hr. Antipyrine, a marker of passive diffusion, was coinfused in all experiments. Blood (5 mL) and CSF samples (0.5-1 mL) were collected by venous and lumbar/thoracic punctures, respectively, at 24 and 28 hr after beginning the infusion. When ZDV and ddI were administered alone, the steady-state CSF/plasma concentration ratios were significantly different from unity (ZDV, 0.20 +/- 0.08; ddI, 0.09 +/- 0.04) and were independent of the plasma concentration (P > 0.05). In contrast, the CSF/plasma concentration ratio of antipyrine (0.82 +/- 0.19) was close but significantly smaller than unity (P > 0.05). The CSF/plasma concentration ratios after simultaneous administration of ZDV and ddI were not significantly different (P > 0.05) from those obtained after administration of the drugs alone. These results suggest that ZDV and ddI are actively transported out of the CSF; however, within the concentration range studied, this efflux is neither saturable nor mutually competitive. Concomitant administration of ZDV and ddI did not produce a systemic interaction in the animals, indicating that the pharmacokinetics of either drug is unaffected by the presence of the other.

Pharmacokinetics of dideoxyinosine in pigtailed macaques (Macaca nemestrina) after intravenous and subcutaneous administration.

Four macaques (Macaca nemestrina; 1 female and 3 males) were administered dideoxyinosine (DDI) at three dose levels (3.2 mg/kg i.v., 10 mg/kg i.v., and 20 mg/kg s.c.). Blood and urine samples were collected during 6-8 h and 24 h after drug administration, respectively. The mean plasma clearance (16.7 +/- 4.9 ml/min/kg), steady-state volume of distribution (1.5 +/- 0.4 L/kg), and terminal plasma half-life (96.8 +/- 7.5 min) did not differ significantly between the two i.v. doses. DDI was eliminated from the body primarily by excretion of the unchanged drug in the urine (74%). The absorption of DDI from the subcutaneous site was complete (bioavailability of 0.91 +/- 0.13) and rapid, with peak plasma concentration obtained at 30 min.

A high-performance liquid chromatographic assay for dideoxyinosine in monkey plasma and urine.

A simple, reliable, reproducible, rapid, and sensitive method for high-performance liquid chromatographic assay of dideoxyinosine (DDI) in macaque plasma and urine is described. The method is capable of detecting 25 ng of DDI on-column.