Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans.

CYP1A1 is a cytochrome P450 family 1 enzyme that is mostly expressed in the extrahepatic tissues. To understand the CYP1A1 contribution to drug clearance in humans, we examined the in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CL_int) for a set of drugs that are in vitro CYP1A1 substrates. Despite being strong in vitro CYP1A1 substrates, 82% of drugs gave good IVIVE with predicted CL_int within 2-3-fold of the observed values using human liver microsomes and hepatocytes, suggesting they were not in vivo CYP1A1 substrates due to the lack of extrahepatic contribution to CL_int. Only three drugs (riluzole, melatonin and ramelteon) that are CYP1A2 substrates yielded significant underprediction of in vivo CL_int up to 11-fold. The fold of CL_int underprediction was linearly proportional to human recombinant CYP1A1 (rCYP1A1) CL_int, indicating they were likely to be in vivo CYP1A1 substrates. Using these three substrates, a calibration curve can be developed to enable direct translation from in vitro rCYP1A1 CL_int to in vivo extrahepatic contributions in humans. In vivo CYP1A1 substrates are planar and small, which is consistent with the structure of the active site. This is in contrast to the in vitro substrates, which include large and nonplanar molecules, suggesting rCYP1A1 is more accessible than what is in vivo. The impact of CYP1A1 on first-pass intestinal metabolism was also evaluated and shown to be minimal. This is the first study providing new insights on in vivo translation of CYP1A1 contributions to human clearance using in vitro rCYP1A1 data.