Preclinical pharmacokinetics of the antitumor antibiotic deshydroxy-sparsomycin in beagle dogs.

Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.

Determination of sparsomycin in plasma and urine of the dog by means of reversed-phase high-performance liquid chromatography and first pharmacokinetic results.

Sparsomycin--an antibiotic with marked cytostatic activity--was the subject of a clinical Phase I study in 1964. The structure of sparsomycin was elucidated in 1970 and its first total synthesis was reported in 1981. Here we describe a sensitive high-performance liquid chromatographic method of determination. The detection limit was found to be 10 ng/ml of plasma and 20 ng/ml of urine. With this procedure sparsomycin and isosparsomycin can readily be separated. In addition, we performed a first pharmacokinetic study in the dog and found a half-life time t1/2 beta of 1.1 h. Only 25% of the administered dose could be recovered in the urine as sparsomycin. We consider that by now many prerequisites for further preclinical studies have been achieved, and the results of these studies will determine whether sparsomycin deserves reintroduction into clinical use.

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs.

N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 beta was 0.2 hours (12 minutes) and t1/2 tau was 0.75 +/- 0.1 hours (45 +/- 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 tau was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.