Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, intravenous, and intraperitoneal administration of cyclophosphamide.

OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4-hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, IV, and IP administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive cyclophosphamide (200 mg/m2) via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration-versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients.

Inhaled flunisolide suppresses the hypothalamic-pituitary-adrenocortical axis, but has minimal systemic immune effects in healthy cats.

Feline bronchial disease is commonly treated with oral glucocorticoids (OGC), which might be contraindicated in cats with certain infectious, endocrine, renal, or cardiac diseases. Inhalant GC (IGC) maximize local efficacy and minimize systemic bioavailability. We evaluated systemic endocrine and immune effects of IGC (flunisolide, 250 microg/puff q12h) versus OGC (prednisone, 10 mg/d PO) and placebo. Six healthy cats received each drug for 2 weeks followed by a 1-month washout. Testing included determination of single early morning cortisol concentration, results of ACTH stimulation, the urine cortisol-to-creatinine ratio (UC: Cr), lymphocyte phenotype, lymphocyte blastogenesis, serum total IgA and IgM concentrations, and cytokine profiles. Significant differences between treatments were not apparent for serum immunoglobulin concentrations, or expression (mRNA) for the cytokines, interleukin (IL-) 2, IL-4, and IL-10, or gamma interferon. Single early morning cortisol concentration was lower for IGC (0.68 - 0.74 microg/dL), compared with that associated with placebo (2.82 +/- 1.94 microg/dL; P = .033). The ACTH-stimulated peak cortisol concentrations were lower after treatment in cats receiving IGC (before, 8.5 +/- 50.2 microg/dL; after, 2.9 +/- 3.3 microg/dL, P = .0004), but not OGC (before, 8.0 +/- 6.1 microg/dL; after, 6.0 +/- 4.5 microg/dL, P = .07). Similarly, UC: Cr (0.8 +/- 0.8) before IGC was lower than the value (5.02 +/- 3.62; P = .019) after IGC. Compared with placebo, cats given OGC, but not IGC, had significantly lower total percentages of T and B cells. Lymphocyte proliferation was decreased in cats receiving OGC, but not IGC, in comparison with placebo (6.9 +/- 3.3; 24.0 +/- 6.5; 18.8 +/- 14.0, respectively). Significantly more IL-10 mRNA transcription was detected in cats administered OGC or IGC, compared with placebo. Although IGC suppress the hypothalamic-pituitary-adrenocortical axis, IGC had minimal effects on the systemic adaptive immune system.

Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma.

BACKGROUND: Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma. METHODS: Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin. RESULTS: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 µM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone. CONCLUSIONS: Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m2 doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m2) appears safe.