title: Monitoring drug-protein interaction.
abstract: A variety of therapeutic drugs can undergo biotransformation via Phase I and Phase II enzymes to reactive metabolites that have intrinsic chemical reactivity toward proteins and cause potential organ toxicity. A drug-protein adduct is a protein complex that forms when electrophilic drugs or their reactive metabolite(s) covalently bind to a protein molecule. Formation of such drug-protein adducts eliciting cellular damages and immune responses has been a major hypothesis for the mechanism of toxicity caused by numerous drugs. The monitoring of protein-drug adducts is important in the kinetic and mechanistic studies of drug-protein adducts and establishment of dose-toxicity relationships. The determination of drug-protein adducts can also provide supportive evidence for diagnosis of drug-induced diseases associated with protein-drug adduct formation in patients. The plasma is the most commonly used matrix for monitoring drug-protein adducts due to its convenience and safety. Measurement of circulating antibodies against drug-protein adducts may be used as a useful surrogate marker in the monitoring of drug-protein adducts. The determination of plasma protein adducts and/or relevant antibodies following administration of several drugs including acetaminophen, dapsone, diclofenac and halothane has been conducted in clinical settings for characterizing drug toxicity associated with drug-protein adduct formation. The monitoring of drug-protein adducts often involves multi-step laboratory procedure including sample collection and preliminary preparation, separation to isolate or extract the target compound from a mixture, identification and determination. However, the monitoring of drug-protein adducts is often difficult because of short half-lives of the protein adducts, sampling problem and lack of sensitive analytical techniques for the protein adducts. Currently, chromatographic (e.g. high performance liquid chromatography) and immunological methods (e.g. enzyme-linked immunosorbent assay) are two major techniques used to determine protein adducts of drugs in patients. The present review highlights the importance for clinical monitoring of drug-protein adducts, with an emphasis on methodology and with a further discussion of the application of these techniques to individual drugs and their target proteins.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Singapore.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Yang
authors.forename: Ze-Ping
authors.initials: ZP
authors.lastname: Hu
authors.forename: Sui Yung
authors.initials: SY
authors.lastname: Chan
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins