In vivo effects of antiviral acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethyl]adenine (adefovir) on cytochrome P450 system of rat liver microsomes.

Interference of antiviral agent adefovir, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with microsomal drug metabolizing system was investigated in rats. The content of total liver cytochrome P450 (CYP) was lowered while that of its denaturated form, P420, was elevated in animals intraperitoneally treated with PMEA (25 mg/kg). Similar effect was observed after treatment with a prodrug of adevofir, adefovir dipivoxil (bisPOM-PMEA). The CYP2E1-dependent formation of 4-nitrocatechol from p-nitrophenol was diminished, though the specific activity of p-nitrophenol hydroxylase remained unchanged. PMEA had no influence on expression of CYP2E1 protein and mRNA and mRNAs of other P450 isoenzymes (1A1, 1A2, 2C11, 3A1, 3A2, and 4A1). It may be concluded that repeated systemic administration of higher doses of PMEA results in a partial degradation of rat CYP protein to inactive P420.

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.

Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.