Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor.
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Liao M, Jaw-Tsai S, Beltman J, Simmons AD, Harding TC, Xiao JJ
Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor.
Xenobiotica. 2020 Sep;50(9):1032-1042. doi: 10.1080/00498254.2020.1737759. Epub 2020 Mar 18.
- PubMed ID
- 32129697 [ View in PubMed]
- Abstract
1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC50, 3.55, 12.9, 5.42, 41.6, and 17.2-22.9 microM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 microM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC50, 169 and 55 microM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibition, respectively) at 300 microM. Rucaparib inhibited OCT1, OCT2, MATE1, and MATE2-K (IC50, 4.3, 31, 0.63, and 0.19 muM, respectively).3. DDI risk assessment using static models suggested potential CYP-related DDIs, with rucaparib as a perpetrator. Caution is advised when co-administering rucaparib with sensitive substrates of MATEs, OCT1, and OCT2.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Rucaparib Cytochrome P450 1A2 Protein Humans NoSubstrateInhibitorInducerDetails Rucaparib Cytochrome P450 2C19 Protein Humans NoInhibitorDetails Rucaparib Cytochrome P450 2C9 Protein Humans NoInhibitorDetails Rucaparib Cytochrome P450 3A43 Protein Humans NoInhibitorDetails Rucaparib Cytochrome P450 3A5 Protein Humans NoInhibitorDetails Rucaparib Cytochrome P450 3A7 Protein Humans NoInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAbemaciclibRucaparib The metabolism of Abemaciclib can be decreased when combined with Rucaparib. AcalabrutinibRucaparib The metabolism of Acalabrutinib can be decreased when combined with Rucaparib. AcenocoumarolRucaparib The metabolism of Acenocoumarol can be decreased when combined with Rucaparib. AlectinibRucaparib The metabolism of Alectinib can be decreased when combined with Rucaparib. AminophyllineRucaparib The metabolism of Aminophylline can be decreased when combined with Rucaparib.