Assessment of the <i>in vitro</i> cytochrome P450 (CYP) inhibition potential of ZYTP1, a novel poly (ADP-ribose) polymerase inhibitor
Creators: name: Giri, Poonam
name: Lakshmikant Gupta
name: Singh, Sanjay
name: Patel, Nirmal
name: Nuggehally R. Srinivas
name: Brijesh Kumar Srivastva
name: Desai, Ranjit C.
name: Patel, Pankaj R.
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biochemistry
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Sociology
subject: FOS: Sociology
subject: FOS: Sociology
subject: Developmental Biology
subject: Cancer
subject: Hematology
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences

description: ZYTP1 is a novel Poly (ADP-ribose) polymerase protein inhibitor being developed for cancer indications.The focus of the work was to determine if ZYTP1 had a perpetrator role in the <i>in vitro</i> inhibition of cytochrome P450 (CYP) enzymes to aid dosing decisions during the clinical development of ZYTP1.ZYTP1 IC<sub>50</sub> for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 was determined using human liver microsomes and LC-MS/MS detection. CYP3A4/5 IC<sub>50</sub> of depropylated metabolite of ZYTP1 was also determined. Time dependent inhibition of CYP3A4/5 by ZYTP1 was also assessed using substrates, testosterone and midazolam.The mean IC<sub>50</sub> values of ZYTP1 were &gt;100 µM for CYP1A2, 2B6 and 2D6, while 56.1, 24.5, 39.5 and 23.3–58.7 µM for CYP2C8, 2C9, 2C19 and 3A4/5, respectively. The CYP3A4/5 IC<sub>50</sub> of depropylated metabolite was 11.95–24.51 µM. Time dependent CYP3A4/5 inhibition was noted for testosterone and midazolam with IC<sub>50</sub> shift of 10.9- and 39.9-fold, respectively. With midazolam, the <i>kinact</i> and <i>KI</i> values of ZYTP1 were 0.075 min<sup>−1</sup> and 4.47 µM for the CYP3A4/5 time dependent inhibition, respectively.Because of potent inhibition of CYP3A4/5, drugs that undergo metabolism via CYP3A4/5 pathway should be avoided during ZYTP1 therapy. ZYTP1 is a novel Poly (ADP-ribose) polymerase protein inhibitor being developed for cancer indications. The focus of the work was to determine if ZYTP1 had a perpetrator role in the <i>in vitro</i> inhibition of cytochrome P450 (CYP) enzymes to aid dosing decisions during the clinical development of ZYTP1. ZYTP1 IC<sub>50</sub> for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 was determined using human liver microsomes and LC-MS/MS detection. CYP3A4/5 IC<sub>50</sub> of depropylated metabolite of ZYTP1 was also determined. Time dependent inhibition of CYP3A4/5 by ZYTP1 was also assessed using substrates, testosterone and midazolam. The mean IC<sub>50</sub> values of ZYTP1 were &gt;100 µM for CYP1A2, 2B6 and 2D6, while 56.1, 24.5, 39.5 and 23.3–58.7 µM for CYP2C8, 2C9, 2C19 and 3A4/5, respectively. The CYP3A4/5 IC<sub>50</sub> of depropylated metabolite was 11.95–24.51 µM. Time dependent CYP3A4/5 inhibition was noted for testosterone and midazolam with IC<sub>50</sub> shift of 10.9- and 39.9-fold, respectively. With midazolam, the <i>kinact</i> and <i>KI</i> values of ZYTP1 were 0.075 min<sup>−1</sup> and 4.47 µM for the CYP3A4/5 time dependent inhibition, respectively. Because of potent inhibition of CYP3A4/5, drugs that undergo metabolism via CYP3A4/5 pathway should be avoided during ZYTP1 therapy.