Zidovudine serum, cerebrospinal fluid, and brain concentrations following chronic administration of a new zidovudine formulation via an implantable pump in dogs [corrected].
Zidovudine (AZT), prepared as an alkaline solution, was administered iv and intraarterially (ia) by continuous infusion via an implantable pump in dogs. The AZT serum and cerebrospinal fluid (CSF) concentrations were measured over a 28-day treatment period by HPLC. Terminal brain AZT concentrations were also measured. Control (vehicle only) animals were also studied. All animals were evaluated for pathological changes associated with the AZT and vehicle infusions in catheterized vessels and other organs. In the iv AZT treatment group, serum AZT concentrations were relatively constant, with individual coefficients of variations (%CV) of 20% or less. Mean CSF:serum and brain:serum AZT concentration ratios were 0.149 and 0.212, respectively. In the ia AZT treatment group, serum AZT concentrations were more variable than in the iv group, with %CV ranging from 22 to 79%. The fluctuations in serum concentrations were attributed to temporary blockages of the outflow catheter. Mean CSF:serum and brain:serum AZT concentration ratios were 0.126 and 0.249, respectively. Pathological changes, similar in both control and treatment groups, included endothelial denudation and myointimal proliferation at the infusion sites. The conclusions of the study are (1) steady-state greater than 1 microM AZT serum concentrations can be maintained chronically by use of an implantable pump containing a basic pH AZT solution; (2) ia delivery of AZT did not increase central nervous system uptake compared with iv administration; and (3) morbidity associated with the infused solutions does not seem to be a limitation for this mode of therapy.
Gallo
J M
JM
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
Sanzgiri
Y
Y
Howerth
E W
EW
Finco
T S
TS
Wilson
J
J
Johnston
J
J
Tackett
R
R
Budsberg
S C
SC
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D015918:Infusion Pumps, Implantable; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008297:Male; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D015215:Zidovudine