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.
Tuntland
T
T
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Ravasco
R J
RJ
al-Habet
S
S
Unadkat
J D
JD
D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D002851:Chromatography, High Pressure Liquid; D016049:Didanosine / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid* / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D008254:Macaca nemestrina; D008297:Male; D015215:Zidovudine / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid* / Q000494:pharmacology
D015215:Zidovudine; D016049:Didanosine; D000983:Antipyrine