Modeling the effects of commonly used drugs on human metabolism

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a
drug. In addition, diet and genetics have a profound effect on cellular metabolism under
health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic
reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives,
immunosuppressants, and analgesics. This reconstruction captures in detail our
current understanding of their absorption, intra-cellular distribution, metabolism, and
elimination. We combined this drug module with the most comprehensive reconstruction of
human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803
metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the
overall drug metabolism of these compounds, we investigated effects of dietary composition
and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main
findings include (i) shift in dietary patterns significantly affect statins and acetaminophen
metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of
mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can
be explained by several common metabolic and transport pathways other than the previously
established CYP3A4 connection. This work holds the potential for studying adverse drug
reactions and designing patient-specific therapies.