In medicine, one size doesn’t fit all and, despite rigorous testing, there is often no way to predict how an individual patient will react to a particular drug. The aim of personalised prescribing is to be able match the right dose of the right drug to the right patient. Although the study of pharmacogenomics – which looks at the influence of the genetic background of the patient on drug efficacy and/or toxicity – shows promise in predicting how different people will respond to a particular drug, it is increasingly being recognised that other factors are also important in determining individual responses. Scientists at Pfizer Research and Development and Imperial College London have previously shown in animal studies that, as well as genetic variations in metabolic pathways, differences in environmental factors also play a role in determining the safety and efficacy of drugs. In an extension of their earlier work, the researchers have now shown that this combined ‘pharmacometabonomic’ approach is also relevant to human patients. The new study used 1HNMR spectroscopy to evaluate the metabolic fate of a single 1g dose of paracetamol (acetaminophen) against the background of a pre-dose urinary metabolite profile in a group of 99 healthy male volunteers aged 18-64. They found that individuals with high pre-dose levels of p-cresol sulphate had low post-dose ratios of paracetamol sulphate to paracetamol glucuronide. p-Cresol is produced from tyrosine by bacteria in the gut and is then converted to the sulphate by the cytosolic sulphotransferase, SULT1A1, using 3-phosphoadenosine 5-phosphosulphate as cofactor. Since paracetamol is a substrate for the same enzyme-cofactor pair, competition by endogenous p-cresol reduces the amount of paracetamol sulphate. Although it remains to be seen whether these findings could explain adverse reactions to paracetamol, sulphonation plays a role in the excretion of many drugs and their hydroxylated metabolites and production of p-cresol in the gut could influence the metabolism, and hence safety and efficacy, of all of these.
Further studies are needed to determine whether an association between pre-dose urinary metabolite profiles and drug metabolism is seen in larger human populations but, if so, the authors suggest that gut bacteria could become the principal targets of future therapies or could be manipulated to improve drug treatment outcomes. The study is published in the Proceedings of the National Academy of Sciences.
Although the study clearly shows that pharmacometabonomics could have value in optimising individual treatments, as with pharmacogenomic profiling, the logistics of collecting and storing personal data upfront so that prescribing is not delayed will be a formidable hurdle.
Increasingly, scientists and doctors are trying to personalise cancer treatment by identifying genetic alterations involved in the disease in individual patients. One example is the development of a monoclonal antibody, trastuzumab (Herceptin™), directed against the ErbB-2 (HER2) protein which is overexpressed in a subset of breast cancers and leads to a highly aggressive form of the disease.
DNA microarrays have been widely used to study gene expression in cancer and a team of US researchers have now used the technique to search for other genes that are overexpressed in breast cancers. Writing in the journal PNAS, the team describe a meta analysis of 31 breast cancer gene profiling studies comprising almost 3,200 microarrays. As well as correctly identifying the known breast cancer-associated gene, ErbB-2, the study found that the angiotensin II receptor type I (AT1) was markedly overexpressed (up to 100-fold) in 10-20% of tumours across multiple independent cohorts. AT1 overexpression was found only in oestrogen receptor (ER)-positive tumours and was also restricted to samples that did not overexpress ErbB-2. In primary mammary epithelial cells, ectopic overexpression of AT1 together with angiotensin II stimulation led to a highly invasive phenotype that was attenuated by the AT1 antagonist, losartan. In mice, treatment with losartan (90 mg/kg/day) for eight weeks was found to reduce tumour growth by 30% in AT1-positive breast cancer xenografts.
AT1 has previously been linked to cancer and cancer-related signalling pathways and the new study suggests that women with AT1-overexpressing breast cancer may benefit from treatment with an AT1 antagonist. Earlier studies have linked polymorphisms in the angiotensin pathway with breast cancer incidence and, although studies have not found a significant relationship between antihypertensive therapy and breast cancer incidence, the authors believe that the studies may not have been sufficiently powered to detect the small changes in incidence that might be expected from a subset of only 10-20% of AT1-positive patients.
Traditionally, prescribing has been on a one-size-fits-all basis, with standardised doses of medicines given to all patients. Personalised medicine offers the promise of more effective therapy with fewer side effects by better understanding the genetic causes of disease and different individual reactions to drug treatment. Genetic variants in the genes encoding the cytochrome p450 enzymes, which activate or degrade many commonly used drugs, are increasingly being linked to variations in response to medicines. Separate reports by Collet et al, Mega et al and Simon et al highlight the importance of CYP2C19 polymorphisms in responsiveness to clopidogrel, an oral antiplatelet agent that is commonly prescribed after heart attacks to reduce the likelihood of subsequent cardiovascular events. Clopidogrel is a pro-drug that is inactive until it is metabolised in the liver by cytochrome P450 enzymes, including CYP2C19. All studies found that individuals with loss-of-function variants of CYP2C19 were more likely to die or experience major adverse cardiovascular events than individuals with fully functional CYP2C19.
The FDA and the International Serious Adverse Events Consortium have also recently released the first data on the genetics associated with serious drug-induced skin rashes, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Understanding which patients are likely to suffer severe reactions to commonly prescribed drugs should reduce the incidence of these life-threatening conditions.