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The tenth annual symposium of the International Isotope Society's United Kingdom Group took place at the Alderley Park site of AstraZeneca plc. The symposium was attended by over 80 delegates from academia, the pharmaceutical and agrochemical industries, life science and fine chemical companies. Delegates were welcomed to the site by Dr Peter Warner of the Medicinal Chemistry Department. The scientific programme consisted of presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with significant implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The programme was split into a morning and afternoon session chaired by Dr John Harding (AstraZeneca, who also organised the excellent domestic programme) and Dr Karl Cable (Glaxo Wellcome). The meeting ended with concluding remarks from Dr Ken Lawrie (SmithKline Beecham), chairman of the UK Group. This years symposium had a larger attendance from other European countries, an excellent level of sponsorship was achieved, and the symposium proved self-financing. The next UK group symposium is planned for early October 2001. Meeting Programme Paul Pringle [University of Bristol, UK] To what extent can Homogeneous Catalysts be Designed? Henrick Olsen [Novo Nordisk, Denmark] Mapping of Pharmaceutical Degradation Products in the Solid Dosage Form using Radiotracers. Marie-Claire Lasne [University of Caen, France] Synthesis of New Ligands of Cholinergic Receptors. Strategies for their Radiolabelling with Positron Emitters, Carbon-11 or Fluorine-18. Christopher Rayner [University of Leeds, UK] Catalysis in Supercritical Carbon Dioxide - What advantages does it have to Offer? Gunnar Antoni, [University of Uppsala, Sweden] Position Specific Labelling of Biomedically Interesting Compounds using Short-Lived Radionuclides. Hugh Wiltshire [Hoffmann-La Roche, UK] The Use of Stable-Labelled Isotopes in Bioequivalence Studies with the HIV-Protease inhibitor Saquinavir. Alison Hill [Kings College, UK] Elucidation of Soraphen A Biosynthesis using2H, 13C and18O-Labelled Precursors. Nick Shipley [Glaxo Wellcome, UK] Preparation of P450 Substrates for use in Drug-drug Interactions Andrew Mather [AstraZeneca, UK] Aspects of Isotopic Labelling by Parallel Chemistry. Helen Booth [Astra Zeneca, UK] Synthesis of14C-labelled forms of a series of Human Leukocyte Elastase Inhibitors.

The development of the collagenase inhibitor, cipemastat (Ro 32-3555), required the synthesis of both carbon-14 labelled and deuteriated material for the measurement of the parent drug and drug-related material in biological fluids. In addition, labelled metabolites were needed for both in vitro metabolism and analytical studies. This paper describes the synthesis of labelled forms of cipemastat and its amide (Ro 32-4778) and glucuronide (Ro 32-6414) metabolites. Copyright © 2001 John Wiley & Sons, Ltd.

The development of the HIV-protease inhibitor, saquinavir (Ro 31-8959), required a range of analytical methods for the measurement of the parent drug and drug-related material in biological fluids. This paper describes the synthesis of 14-carbon and tritium labelled compounds used for in vivo and in vitro investigations of the absorption and disposition of saquinavir in animals and man. It also discusses the preparation of saquinavir labelled with deuterium and stable isotopes of carbon and nitrogen. These forms of the drug were needed for bioequivalence studies in which HPLC/MS/MS was employed for the measurement of plasma concentrations. Finally, the synthesis of a 125-iodine labelled tracer used in a radioimmunoassay for saquinavir is described. Copyright © 1998 John Wiley & Sons, Ltd.

Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.

1. The metabolism of mibefradil has been examined in rat, marmoset, cynomolgus monkey and man after single and multiple oral administration. 2. Metabolites typically represent between 50 and 80% of the circulating drug-related material after single oral doses of mibefradil to man, rat and marmoset. They arise by a combination of enzymatic processes: cytochrome P450-mediated oxidation at saturated and unsaturated carbon atoms, cytochrome P450-catalysed dealkylation and hydrolysis of the ester side-chain. 3. Plasma levels of mibefradil in the cynomolgus monkey are extremely low as a result of very efficient first-pass hydrolysis of its side-chain to give the corresponding alcohol. Steady-state concentrations of this metabolite are comparable with those of the parent drug in man and marmoset, but are relatively low in rat plasma. 4. Hydroxylation at the benzylic carbon of the tetrahydronaphthyl ring leads to further important metabolites in primates, whereas the products of O- and N-demethylation are found in small amounts in all four species. 5. Estimates of the exposure of the various species to the principal metabolites indicate that the choice of the rat, marmoset and cynomolgus monkey for the toxicological assessment of mibefradil was appropriate.

1. The calcium antagonist, Ro 40-5967, is metabolized to a multitude of products by the rat and drug-related material is excreted predominantly via the bile. 2. Diode-array u.v. spectroscopy, following reverse phase h.p.l.c. separation of the partially purified metabolites, has been used to classify these compounds into six spectral classes which have been correlated with different metabolic reactions. 3. Connection of a mass spectrometer directly to the h.p.l.c. equipment by a thermospray interface, produced useful mass spectra. These, together with the u.v. spectra, enabled the structures of many metabolites to be elucidated. 4. Confirmation of structural assignments was provided by n.m.r. spectra of the major metabolites. 5. Major metabolic pathways included N-demethylation (16% of the biliary metabolites), hydrolysis of the ester side-chain (32%), hydroxylation at 4- (19%) and 5- (29%) positions of the benzimidazole ring, aromatization of the tetrahydronaphthyl system (26%), loss of the benzimidazole (15%) and glucuronidation of hydroxyl groups (81%).