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Notes: Abstract  The purpose of the present study was to define the plasma pharmacokinetics, bioavailability, and tissue distribution in mice of halomon, a halogenated monoterpene from Portieria hornemanii that is active in vitro against brain-, renal-, and colon-cancer cell lines. Halomon formulated in cremophor : ethanol : 0.154 M NaCl (1 : 1 : 6, by vol.) was injected i.v. at 20, 60, 90, or 135 mg/kg into female CD2F1 mice. Doses of 135 mg/kg were also given i.p., s.c., and by enteral gavage to female CD2F1 mice and i.v. to male CD2F1 mice. Plasma halomon concentrations were measured with a gas-chromatography system using electron-capture detection. Halomon concentrations were also determined in the brains, hearts, lungs, livers, kidneys, spleens, skeletal muscles, fat, red blood cells, and, if present, testes of mice given 135 mg/kg i.v. Halomon plasma pharmacokinetics were well fit by a two-compartment, open linear model and were linear between 20 and 135 mg/kg. Population estimates of parameters describing halomon plasma pharmacokinetics in female CD2F1 mice were developed with a standard two-stage technique and also by simultaneous modeling of data from 20-, 60-, 90-, and 135-mg/kg i.v. studies in female mice. Halomon bioavailability was 45%, 47%, and 4% after i.p., s.c., and enteral dosing, respectively. Urinary excretion of the parent compound was minimal. Halomon was distributed widely to all tissues studied but was concentrated and persisted in fat. Halomon concentrations measured in the brain were comparable with concomitant concentrations detected in plasma and most other tissues. These data and models are helpful in the simulation and evaluation of conditions produced by preclinical screening and toxicology studies.

Notes: Abstract  The pharmacokinetics of 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane (BE-4-4-4-4) were determined in CD2F1 female mice after administration of i.v. bolus doses of 20 mg/kg (approximately the dose lethal to 10% of the study animals, ∼LD10) as well as 15, 10, and 5 mg/kg and after s.c., i.p., or p.o. doses of 20 mg/kg. BE-4-4-4-4 in plasma and urine was derivatized with dansyl chloride and measured by gradient high-performance liquid chromatography (HPLC) with fluorescence detection. Data were modeled by noncompartmental and compartmental methods. The declines observed in plasma BE-4-4-4-4 concentrations after i.v. delivery of 20, 15, 10, and 5 mg/kg were modeled simultaneously using an interval of 2000 min between doses and were best approximated by a two-compartment, open, linear model. The time courses of plasma BE-4-4-4-4 concentrations after i.p. and s.c. delivery were fit best by a two-compartment, open, linear model with first-order absorption. Peak plasma concentrations of BE-4-4-4-4 measured following an i.v. dose of 20 mg/kg ranged between 30 and 33 μg/ml, the terminal elimination half-life was 94 min, and the volume of distribution (Vdss) was 850 ml/kg. The plasma pharmacokinetics of BE-4-4-4-4 were linear with dose. BE-4-4-4-4 (0.5 and 2.0 μM) in mouse plasma was approximately 67% protein-bound. Bioavailabilities after i.p., s.c., and p.o. delivery were 40%, 50%, and approximately 3%, respectively. Urinary excretion of parent BE-4-4-4-4 in the first 24 h after dosing accounted for less than 30% of the delivered dose. As BE-4-4-4-4 proceeds toward and undergoes clinical evaluation, the data and analytical method presented herein should prove useful in formulating a dose-escalation strategy and, possibly, evaluating toxicities encountered.

Notes: Abstract Purpose: Pc4 is a silicone phthalocyanine photosensitizing agent that is entering clinical trials. Studies were undertaken in mice to develop a suitable formulation and analytical methodology for use in pharmacokinetic studies and to define the plasma pharmacokinetics, tissue distribution, and urinary excretion of Pc4 after i.v. delivery. Methods: An HPLC method suitable for separation and quantification of Pc4 was developed and validated for use in mouse plasma, tissues, and urine. The stability of Pc4 was characterized in a variety of formulations as well as in mouse plasma. Before pursuing pharmacokinetic studies, preliminary toxicity studies were undertaken. These studies utilized Pc4 formulated in diluent 12:0.154 M NaCl (1:3, v:v). Pharmacokinetic studies involved Pc4 doses of 40 mg/kg, 10 mg/kg and 2 mg/kg administered as i.v. boluses to female, CD2F1 mice . Doses of 40 mg/kg, 10 mg/kg, and 2 mg/kg were studied with drug formulated in diluent 12:0.154 M NaCl (1:3, v:v). Doses of 10 mg/kg and 2 mg/kg were also studied with drug formulated in a vehicle consisting of polyethylene glycol:Tween 80:0.01 M sodium phosphate buffer, pH 7.0 (40:0.2:59.8, v:v:v). Compartmental and non-compartmental analyses were applied to the plasma concentration-versus-time data. Concentrations of Pc4 were also determined in a variety of tissues, including brain, lung, liver, kidney, skeletal muscle, skin, heart, spleen, and abdominal fat. Urine was collected from animals treated with each of the doses of Pc4 mentioned above, and daily, as well as cumulative drug excretion was calculated until 168 h after treatment. Results: At a dose of 80 mg/kg, two of five male and two of five female mice were dead by 24 h after injection. Pathologic examination revealed gross findings of blue discoloration affecting many tissues, with lungs that were grossly hemorrhagic and very blue-black. Microscopic examination of the lungs revealed mild acute interstitial pneumonia, with perivascular edema and inflammation, and a detectable margination of neutrophils around larger pulmonary blood vessels. Animals sacrificed 14 days after treatment showed mild granulomatous pneumonia, characterized by clusters of multi-nucleated giant cells, with fewer macrophages and neutrophils. The giant cells frequently contained phagocytized particles, which were clear and relatively fusiform. All mice treated with 40 mg/kg or 20 mg/kg survived and returned to pretreatment weight during the 14 days after treatment. Intravenous bolus delivery of Pc4, at a dose of 40 mg/kg, produced “peak” plasma Pc4 concentrations between 7.81 and 8.92 μg/ml in mice killed at 5 min after injection (the earliest time studied after drug delivery). Sequential reduction of the Pc4 dose to 10 mg/kg in diluent 12:0.154 M NaCl (1:3, v:v), 10 mg/kg in polyethylene glycol:Tween 80:sodium phosphate buffer (40:0.2:59.8, v:v:v), 2 mg/kg in diluent 12:0.154 M NaCl (1:3, v:v), and, finally, 2 mg/kg in polyethylene glycol:Tween 80:sodium phosphate buffer (40:0.2:59.8, v:v:v) resulted in “peak” plasma Pc4 concentrations between 2.07 and 3.24, 0.68 and 0.98 μg/ml, and 0.29 and 0.41 μg/ml, respectively. Pc4 persisted in plasma for prolonged periods of time (72–168 h). Non-compartmental analysis of plasma Pc4 concentration-versus-time data showed an increase in area under the plasma Pc4 concentration-versus-time curve (AUC) when the dose of Pc4 increased from 2 mg/kg to 40 mg/kg. Across the 20-fold range of doses studied, total body clearance (CLtb) varied from 376 to 1106 ml h−1 kg−1. Compartmental modeling of plasma Pc4 concentration versus time data showed the data to be fit best by a two-compartment, open, linear model. Minimal amounts of Pc4 were detected in the urine of mice. After i.v. bolus delivery to mice, Pc4 distributed rapidly to all tissues and persisted in most tissues for the duration of each pharmacokinetic study. Tissue exposure, as measured by AUC, increased in a dose-dependent fashion. Conclusions: The HPLC method developed for quantification of Pc4 in plasma, urine, and tissues should be suitable for clinical studies of the drug. Pc4 is widely distributed and persists in plasma and tissues of mice for prolonged periods of time. These data are relevant to the design of forthcoming clinical trials of Pc4.