Title page for ETD etd-03232005-135825


Document Type Master's Dissertation
Author Miller, David B
URN etd-03232005-135825
Document Title The pharmacokinetics of Diminazene Aceturate after intramuscular and intravenous administration in the healthy dog
Degree MMedVet(Med)
Department Companion Animal Clinical Studies
Supervisor
Advisor Name Title
Dr L S Jacobson
Prof R A Lobetti Supervisor
Keywords
  • no key words available
Date 2003-03-06
Availability unrestricted
Abstract
Diminazene is the therapy of choice for canine babesiosis in South Africa. Differences in the dosage described for diminazene usage and the occurrence of mortality at doses equal to or close to the recommended treatment dose for the treatment of canine babesiosis have been described. This has necessitated the need to more fully understand the absorption and disposition of diminazene in dogs.

An intravenous (i.v.) as well as an intramuscular (i.m.) pharmacokinetic study was conducted to determine the pharmacokinetics of diminazine in healthy dogs as well as to describe the binding characteristics of diminazine (in the blood) in vivo and in vitro.

Diminazene pharmacokinetics showed a large inter-individual variation after i.m. administration at 4.2 mg/kg (% CV 37 163) with a rapid absorption (K01-Hl - 6.6 + 10.8 min resulting in a Cmax of 1849 + 268.7 ng/ml at Tmax of 20 min. There was a rapid distribution phase (Ta 21.6 + 11.4 min) with the distribution into the peripheral compartment being more rapid than the distribution back in to the central compartment. A mean elimination half-life (Tb 5.31 + 3.89 h) was derived. At 1 h after i.m. injection, 75 % of the diminazene in whole blood was in the plasma fraction. Compartmental analysis of the i.v. data after diminazene administration at 2 mg/kg revealed a Cmax of 3725 + 1672.8 ng/ml with a rapid distribution phase (Ta 7.0 + 6.2 min) with a long elimination half-life (Tb - 32.0 28.8 h).

The distribution into the peripheral compartment was more rapid than the distribution back into the central compartment as measured by K12 and K21 (K12 - 8.78 + 8.71; K21 0.32 + 0.25). The i.v. pharmacokinetic results were very variable between the dogs with a % CV of 55.5 137.2.

We hypothesize that the rapid distribution phase is a result of diminazene being sequestered into the liver, followed by a slow terminal phase were diminazene is both redistributed to the peripheral tissues and renally excreted. The Tb of 32.0 28.8 h in the i.v. study is considerably longer than the elimination half-life (Tb - 5.31 + 3.89 h) found in the i.m. study. This is most likely due the 25 ng/ml limit of detection of the HPLC, detecting the i.v. tail but not the i.m. tail. This is not surprising as the Cmax levels following i.v administration were more than 2 times higher than after i.m. administration.

Further pharmacokinetic studies with diminazene in dogs should take account of the rapid absorption of diminazene after i.m. administration and the low levels of diminazene in the terminal phases. The initial sequestration of diminazene in the liver and distribution to the peripheral compartment needs further clarification. With the knowledge gained of the pharmacokinetics of diminazene in healthy dogs, a population pharmacokinetic study in dogs with babesiosis is recommended. This will allow us to more fully appreciate alterations in the pharmacokinetics of diminazene in diseased populations and the potential covariants exerting an effect.

It is our current recommendation that diminazene given i.m. at 4.2 mg/kg not be repeated within a 21 day period.

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