In vitro evaluation of the inhibition and induction potential of olaparib, a potent poly(ADP-ribose) polymerase inhibitor, on cytochrome P450.

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McCormick A, Swaisland H, Reddy VP, Learoyd M, Scarfe G

In vitro evaluation of the inhibition and induction potential of olaparib, a potent poly(ADP-ribose) polymerase inhibitor, on cytochrome P450.

Xenobiotica. 2018 Jun;48(6):555-564. doi: 10.1080/00498254.2017.1346332. Epub 2017 Jul 25.

PubMed ID

28657402 [ View in PubMed

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Abstract

1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory effects were determined in human liver microsomes (HLM); inductive effects were evaluated in cultured human hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 and caused slight inhibition of CYP2C9, CYP2C19 and CYP3A4/5 in HLM up to a concentration of 100 muM. However, olaparib (17-500 muM) inhibited CYP3A4/5 with an IC50 of 119 muM. In time-dependent CYP inhibition assays, olaparib (10 muM) had no effect against CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 and a minor effect against CYP3A4/5. In a further study, olaparib (2-200 muM) functioned as a time-dependent inhibitor of CYP3A4/5 (KI, 72.2 muM and Kinact, 0.0675 min(-1)). Assessment of the CYP induction potential of olaparib (0.061-44 muM) showed minor concentration-related increases in CYP1A2 and more marked increases in CYP2B6 and CYP3A4 mRNA, compared with positive control activity; however, no significant change in CYP3A4/5 enzyme activity was observed. 3. Clinically significant drug-drug interactions due to olaparib inhibition or induction of hepatic or intestinal CYP3A4/5 cannot be excluded. It is recommended that olaparib is given with caution with narrow therapeutic range or sensitive CYP3A substrates, and that prescribers are aware that olaparib may reduce exposure to substrates of CYP2B6.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Olaparib	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Olaparib	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate Inhibitor	Details