Predicting drug metabolism: experiment and/or computation?

Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism. We highlight the scope and limitations of these methods, and indicate strategies to harvest the synergies that result from combining measurement and prediction of drug metabolism.

Hepatic Manifestations of Wilson Disease - CHUV Experience 2005-2010

Background and aim: Wilson disease (WD) is an inherited disorder ofhepatic copper excretion leading to toxic accumulation of copper in theliver as well as the brain, cornea, and other organs. The defect is due tomutations of the copper-transporting ATPase ATP7B. Here, we describethe adult cases of hepatic WD diagnosed at the CHUV between 2005and 2010.Methods: Clinical manifestions, results of diagnostic tests, and follow-upof adult patients with hepatic WD were recorded systematically.Results: Seven new adult cases of hepatic WD were diagnosed in ourcenter between 2005 and 2010. Three were women and 4 men, with amedian a ge at d iagnosis o f 24 (range, 1 8-56) years. Three patientspresented with acute liver failure (ALF), three with persistently elevatedliver function tests, and one with a dvanced cirrhosis. None hadneurological manifestations. Only one patient, presenting with ALF, had aKayser-Fleischer corneal ring. Median ceruloplasmin levels at diagnosiswere 0.13 (range, <0.03-0.30) g/l, median 24 h urinary copper excretion6.3 (range, 0.4-62.0) μmol/24 h, and median hepatic copperconcentration 591 (range, 284-1049) μg/g. At least one mutation in theATP7B g ene was i dentified in a ll patients. Allelic frequency of t hecommon H1069Q mutation was 14%. Two patients presenting with ALFand the one with advanced cirrhosis underwent successful l ivertransplantation. One patient with ALF recovered under chelator therapy.D-penicillamine was used as first-line chelator treatment, with a switch totrientine due to adverse effects in 2 out of 4 patients u nder l ong-termtreatment.Conclusions: The clinical presentation of WD and the performance ofdiagnostic tests are variable. A high index of suspicion i n clinicallycompatible situations i s key, with a combination of tests allowing thediagnosis of WD.

La maladie de Wilson: un caméléon clinique auquel il faut penser [A primer on Wilson disease for the general practitioner].

Wilson disease (WD) is an inherited disorder of hepatic copper excretion leading to toxic accumulation of copper in the liver as well as the brain, cornea, and other organs. The defect is due to mutations of the copper-transporting ATPase ATP7B. Clinical manifestations are highly variable and comprise acute liver failure, chronic hepatitis and cirrhosis as well as neurological or psychiatric symptoms. The Kayser-Fleischer corneal ring is pathognomonic but absent in about 50% of patients with hepatic manifestations alone. A high index of suspicion in clinically compatible situations is key, with a combination of laboratory tests allowing the diagnosis of WD. Treatment is based on the use of chelating agents, D-penicillamine or trientine. Liver transplantation should be considered for patients with acute liver failure or advanced cirrhosis.