title: Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen-induced toxicity in humans.
abstract: Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP-induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice.
authors.affiliation: Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Thiel
authors.affiliation: Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Cordes
authors.affiliation: Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Baier
authors.affiliation: Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: L M
authors.initials: LM
authors.lastname: Blank
authors.affiliation: Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Kuepfer
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000493:pharmacokinetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000493:pharmacokinetics; D002110:Caffeine / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000517:prevention & control; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008954:Models, Biological; D010146:Pain / Q000188:drug therapy; D057285:Precision Medicine
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D002110:Caffeine