Anitha Saravanakumar* , University of Rhode Island, Kingston, RI
Armin Sadighi , Biomedical and Pharmaceutical Sciences, Kingston, Rhode Island
Rachel Ryu , University of Rhode Island, Kingston, RI
Fatemeh Akhlaghi , University of Rhode Island, Kingston, RI
Members of cytochrome P450 (CYP) family are the major enzymes involved in drug metabolism and pharmacokinetics. However, a shift in non-P450 metabolism has been reported for newer agents. The objective of this study was to systematically analyze the contribution of P450 and non-P450s to the metabolism of FDA approved drugs from 2005-2016 in comparison with top 200 most prescribed medications in the US market. Information was extracted from the University of Washington Drug Interaction Database© as well as other internet based resources and primary research articles. A total of 593 compounds (127 Biologics and 466 Small molecules (SMs)), were FDA approved between 2005-2011. The SMs were administered by the following routes: systemic (91%) and non-systemic (9%). Non-systemic routes included topical (38%), inhalation (27%), ophthalmic (18%), subcutaneous (5%), vaginal (4%), nasal (4%), buccal (2%), and local injection (2%). Major and minor metabolism pathways were determined according to the FDA guidelines among the SMs that are administered systematically. Major metabolism contribution was by P450 (55%) and non-P450 (17%). P450 isoform contribution was CYP3A4/5 (52%), 2D6 (11%), 2C9 (8%), 1A2 (7%), 2C19 (7%), 2C8 (6%), and 2E1 (1%) and other P450s (8%). Non-P450 mediated metabolism was mediated by carboxylesterase (28%), other esterases (31%), monoamine oxidase (11%), alcohol dehydrogenase (11%), flavin-containing mono oxidase (8%), aldehyde oxidase (5%), xanthine oxidase (3%), and aldehyde dehydrogenase (3%). Major metabolism via phase 2 enzymes were UGT (75%) and SULT (25%). The isoform contribution of UGTs were 1A1 (12%), 2B7 (12%), 1A9 (10%), 1A3 (6%), 1A4 (5%), 1A6 (4%), 1A8 (4%), 2B4 (4%), 1A10 (3%), 1A7 (1%), and 2B15 (1%). Minor metabolism contribution was by P450 (41%) and non-P450 (2%). CYP isoform contribution was identified as 2D6 (20%), CYP 3A4/5 (19%), 2C19 (14%), 2C9 (13%), 1A2 (9%), 2C8 (7%), 2E1 (2%). Non-P450 mediated metabolism as minor pathway was flavin-containing monooxidase (28%), carboxylesterase (18%), monoamine oxidase (18%), and aldehyde dehydrogenase (9%). Minor metabolism via phase 2 enzymes were contributed by UGT (85%) and SULT (15%). The isoform contribution of UGTs were 1A1 (17%), 1A3 (17%), 1A9 (13%), 2B7 (8%), 1A7 (6%), 1A8 (4%), 2B15 (4%), 2B4 (2%), 1A4 (2%), and 2B17 (2%). Role of transporters as determined by in vitro studies showed significant contribution from uptake (67.6%) and efflux transporters (32.4%) to disposition of SMs. Major uptake transporters were OATP1B1 (27%), OATP1B3 (19%) and OAT3 (13%) and major efflux transporters were P-gp (71%), BCRP (18%) and MRP2 (5%) did. In comparison to previous reports,1 there is a meaningful shift from non-CYP mediated metabolism.

[1] Rendic S, Guengerich FP. Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals. Chem Res Toxicol. 2015 Jan 20; 28(1):38-42.

*Anitha Saravanakumar and Armin Sadighi contributed equally to this work.