ADME

A model for predicting likely sites of CYP3A4-mediated metabolism on drug-like molecules. Singh, S. B., Shen, L. Q., Walker, M. J. & Sheridan, R. P. J. Med. Chem. 46, 1330–1336 (2003)

Oral bioavailability of a drug depends largely on its ability to withstand degradation by intestinal and hepatic metabolizing enzymes,such as cytochrome P450s (CYPs),and there is considerable interest in computational approaches that can efficiently predict compound susceptibility to metabolism. Sheridan and colleagues have developed a model that can rapidly and accurately predict likely sites of metabolism for compounds that could be substrates of CYP3A4.

Anticancer Drugs

PPAR-γ receptor ligands: novel therapy for pituitary adenomas. Heaney, A. P., Fernando, M. & Melmed, S. J. Clin. Invest. 111, 1381–1388 (2003)

Pituitary tumours cause considerable morbidity as a result oflocal invasion and hormonal hypersecretion,but in many cases there is no suitable drug treatment.Heaney and colleagues found that a nuclear receptor known as peroxisome-proliferator-activated receptor-γ (PPAR-γ) is abundantly expressed in human pituitary tumours,and showed that thiazolidinediones — PPAR-γ ligands that are used for treating type 2 diabetes — inhibit pituitary tumour growth and hormone secretion.These drugs could therefore represent a novel treatment for this cancer.

Cardiovascular Disease

Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia. A prospective, randomized, double-blind trial. Ballantyne, C. M. et al. Circulation Apr 28 (2003) doi: 10.1161/01.CIR.0000068312.21969.C8

Although the efficacy ofstatins in reducing levels oflow-density lipoprotein cholesterol (LDL-C) is well established,many patients do not achieve recommended LDL-C goals for several reasons, including increasedrisk ofadverse effects with high statin doses. The results ofthis trial indicate that co-administration of atorvastatin and ezetimibe — the first in a new class of cholesterol-lowering drugs — is significantly more effective in reducing LDL-C than either drug alone.

Anticancer Drugs

Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Cheok, M. H. et al. Nature Genet. 34, 85–90 (2003)

To elucidate how cancer cells respond to chemotherapies,Cheok et al. analysed the effects oftreatment with methotrexate and mercaptopurine alone or in combination on more than 9,600 human genes in acute lymphoblastic leukaemia cells.Their results indicate that changes in gene expression are treatment-specific and that treatment-induced changes in gene expression might provide a basis for optimizing combination chemotherapy.