Pharmacokinetic interaction between intravenous 2',3'-dideoxyinosine and pentamidine in rats.
OBJECTIVE
This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddI) and pentamidine.


BACKGROUND
ddI and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs.


METHODS
ddI (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay.


RESULTS
Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddI from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddI from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddI distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddI coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003).


CONCLUSIONS
These data indicate that pentamidine increased the distribution of ddI into pancreas and muscle, whereas ddI increased the renal elimination of pentamidine.
Yeh
T K
TK
Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus 43210, USA.
Kang
H J
HJ
Wientjes
M G
MG
Au
J L
JL
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004347:Drug Interactions; D005260:Female; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010419:Pentamidine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011863:Radioimmunoassay; D051381:Rats; D011916:Rats, Inbred F344; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D000981:Antiprotozoal Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D010419:Pentamidine; D016049:Didanosine