Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200-250 mg/m² over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h^-1 ; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200-250 mg/m² .

A 3-year-old dog was referred to the Veterinary Medical Teaching Hospital of the University of California-Davis for further evaluation of episodes of epistaxis of 1-year duration and peripheral lymphadenopathy. The patient had a history of atopic dermatitis with no travel history outside of California. Hyperglobulinemia with a polyclonal gammopathy was noted on serum protein electrophoresis. Microscopic evaluation of a bone marrow aspirate sample revealed many free and intra-cellular amastigotes of Leishmania sp. that was further confirmed by qPCR as L infantum. This is, to the best of our knowledge, the first reported case of canine leishmaniasis in the state of California. The patient is believed to have been vertically infected from the dam who is from Serbia and remained subclinical until presentation. Because the clinical progression of leishmaniasis is variable, it is important that precautions be discussed with owners acquiring puppies with dams from endemic regions of leishmaniasis to prevent zoonotic exposure in states where competent vectors are present.