Chapter 6
Pharmacokinetics and Toxicity of a p-Boronophenylalanine-Cyclodextrin Formulation Delivered by Intravenous Infusion to Dogs Downloaded by NATL UNIV OF SINGAPORE on March 28, 2017 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0545.ch006
1
2
3
T. R. LaHann , W. F. Bauer , P. Gavin , and D. R. L u 1
4
Center for Toxicology Research and College of Pharmacy, Idaho State University, Pocatello, ID 83209 Idaho National Engineering Laboratory, Idaho Falls, ID 83415 College of Veterinary Medicine, Washington State University, Pullman, WA 99164 College of Pharmacy, University of Georgia, Athens, GA 30602 2
3
4
Boron-neutron capture therapy (BNCT) is a potentially important treatment for metastatic malignant melanoma. Effective B N C T requires the selective uptake of a boron compound by tumor cells. Para-boronophenylalanine (BPA) is of particular interest for B N C T since it is selectively delivered to melanoma tissue. However, its use is limited by its poor solubility in water at physiological p H . T o facilitate the delivery of B P A to melanoma tissue sites, B P A ' s aqueous solubility was increased by forming a host-guest complex with 2-hydroxypropyl-β-cyclodextrin (ΗΡ-ß-CD). An in vivo study was carried out in dogs to examine B P A levels in plasma and selected tissues after i.v. infusion of B P A . TwoBPAformulations were used: B P A in a p H 7.4 phosphate buffer and in an HP-ß-CD formulation. The pharmacokinetic profiles of BPA i n both formulations were determined. The plasma concentrations of boron for the BPA/HP-ß-CD formulation were much higher than those for the BPA/buffer formulation. The area under each plasma boron concentration-time curve for BPA/HP-ß-CD was 20.7 times that for BPA/buffer. Thus, the delivery of BPA into the blood circulation was significantly enhanced due to the increase in B P A solubility. The incidence of melanoma in Europe, Australia and North America has increased dramatically over the last twenty years. For example, in the U.S., the incidence of melanoma increased 83% between 1973 and 1987 (1), and is currently increasing at a rate of about 3% per year (2). Current therapies for malignant melanoma are effective i n the early stages of the disease, but are of h'mited usefulness i n later
0097-6156/94/0545-0066$08.00/0 © 1994 American Chemical Society
Ottenbrite; Polymeric Drugs and Drug Administration ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
6. LAHANN ETAL.
BPA-CD Formulation Delivered Intravenously to Dogs
stages (3). Not surprisingly, new approaches to treating melanoma are of increasing interest. Recent animal and clinical experiments indicate that boron neutron capture therapy (BNCT) can successfully treat malignant melanoma (4,5,6) and may, in fact, be particularly effective in the treatment of large or metastasized tumors. The underlying concept of using B N C T for the treatment of cancer is that if a compound containing boron can be selectively delivered to a tumor, the boron can be activated by an external neutron source. When the boron captures a slow moving (thermal) neutron, the absorbed energy causes the boron to fission into a lithium and a helium ion. These high energy fission products travel only very short distances, usually less than the diameter of a single cell. Mitochondria, lysosomes and D N A of the cells containing large numbers of boron atoms can be severely damaged by these fission products, and this, in turn, can lead to death of the cell. Effective B N C T requires that 1) tumor cells selectively accumulate a boron-containing drug, and 2) neutrons of sufficient velocity can penetrate to the level of the tumor to activate the boron. P-boronophenylalanine (BPA, Figure 1)
Downloaded by NATL UNIV OF SINGAPORE on March 28, 2017 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0545.ch006
10
10
Figure 1. Chemical structure of p-boronophenylalanine. is the drug most often used as a boron delivery system for malignant melanoma. B P A was initially proposed as a boron delivery drug because it was postulated that this amino acid analog, by mimicking a melanin precursor, would selectively accumulate in melanoma cells. Research indicates that B P A does selectively accumulate in melanocytes (7,8), apparently being taken up by an amino acid transport system. Current evidence, however, suggests that B P A is not incorporated into melanin (7,9). For successful B N C T , tumor boron concentrations of at least 20 ppm are thought to be necessary, but higher tumor boron levels are desirable. Calculations 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 (10). Thus, even modest increases in the amount of boron in tumor cells can dramatically improve the effectiveness of B N C T as a cancer treatment. A major limitation of B P A is that, at physiological p H , it is poorly soluble in water, so that parenteral administration yields low and/or variable tumor boron levels. If uptake by an amino acid transport system is primarily responsible for accumulation of B P A , then high extracellular concentrations of B P A should increase the amount of B P A entering melanocytes. A n i.v. infusion of B P A is the simplest route for delivering B P A to the tumor cells, but is not widely used because of BPA's poor solubility in aqueous solution (
