Cardiovascular Toxicities Associated with Intravenous Administration of P-Boronophenylalanine Formulations
10Boronophenylalanine (BPA) has been shown to be an effective boron delivery drug for boron neutron capture therapy (BNCT) of experimental and spontaneously occurring cancers1. For successful BNCT, tumor boron concentrations of at least 20 ppm are thought to be necessary, but higher tumor boron levels are desirable. Calculations2 indicate that for a given neutron exposure, each doubling of the tumor boron concentration should increase tumor cell kill by a factor of about 10,000. Thus, significant therapeutic benefit would be achieved by delivering the largest possible dose of BPA to tumor. Factors that limit the amount of BPA deliverable to tumor are 1) the aqueous solubility and 2) the intrinsic toxicity of the BPA. BPA is poorly soluble in aqueous solution (<4 g/L at pH 7.4), but formation of a BPA-fructose complex dramatically improves water solubility3 and allows delivery of high levels of boron to tissues3. Little is known about the toxicity of BPA, in part because its poor water solubility has made it difficult to deliver large amounts of drug to animal tissues. Soloway et al.4, Mishima et al.5, Taniyama et al. 6 and Meek7 have all studied the acute toxicity of BPA. Reported LD50 values for BPA ranged from 640 mg/kg6 (i.p., pH 10 solution, rats) to 1,520 mg/kg4 (i.v., pH 10 solution, mice). Chronic oral and s.c. dosing of BPA suspensions was well tolerated7, although the apparent safety of BPA suspensions may more reflect BPA’s relative insolubility at physiological pH than its intrinsic toxicity profile. Nevertheless, the prevailing view seems to be that BPA is a relatively safe drug. While assessing the biodistribution of novel BPA-cyclodextrin formulations, we noted that i.v. infusion of this formulation could impair cardiovascular and pulmonary function in dogs8. To better understand the significance of such an observation, we undertook a study of the effects of high dose BPA infusions on the function of the cardiovascular and pulmonary systems. In this paper, we report the approximate maximally tolerated dose for i.v. infusion of a BPA-fructose complex and the effects of high dose BPA infusions on cardiovascular function in the rat.
KeywordsToxicity Boron Respiration Fructose Mannitol
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- 3.LaHann, T., Lu, D., Sills, C., Daniell, G., Kraft, S., Gavin, P. & Bauer, W. (in press) Bioavailability of Intravenous Formulations of p-BPA in Dog and Rat, in Proceedings of the Fifth International Symposium on Neutron Capture Therapy, eds. Barth, R. & Soloway A. (Plenum Press, New York).Google Scholar
- 4.Soloway, A., Wright, R. & Messer, J. (1961) Evaluation of Boron Compounds for Use in Neutron Capture Therapy of Brain Tumors. J. Pharmacol. Exp. Therap. 134,117–122.Google Scholar
- 5.Mishima, Y., Kakihana, H., Okamoto, M., Yoshino, K. & Konno, K. (filed 1979) Auxiliary Agents for Neutron Capture in Skin, Japanese Patent Application 30209–1979. Google Scholar
- 7.Meek, A. (1988) Investigational New Drug Application for p-Boronophenylalanine, United States Food and Drug Administration Investigational New Drug Application.Google Scholar
- 8.LaHann, T., Bauer, W., Gavin, P. and Lu, D. (in press) Pharmacokinetics and toxicity of a pboronophenylalanine-cyclodextrin formulation delivered by i.v. infusion to dogs, in Polymeric Drugs and Drug Delivery Systems, ed. Ottenbrite, R. (American Chemical Society, Washington).Google Scholar