Soy Protein Containing Diet Attenuates Murine Drug Exposure and Activity via Hepatic and Intestinal Cytochrome P450 Induction

Abstract

Pharmacokinetic variability in drug plasma exposure between different studies within the same species is not unexpected due to a variety of factors (such as differences in formulation, active pharmaceutical ingredient salt form and solid-state, genetic strain, sex, environmental, disease status, bioanalysis methods, circadian rhythms, etc.) although variability from within the same research group typically does not occur to a great degree because these variables are commonly controlled. Surprisingly, a pharmacology proof of concept study with a previously validated tool compound from the literature failed to show expected response in murine glucose-6-phosphate isomerase-induced arthritis model which was tied to compound plasma exposure unexpectedly 10-fold lower than exposure observed from early pharmacokinetic study confirming adequate exposure prior to proof of concept. A systematic series of studies were conducted to investigate causes for exposure difference between pharmacology and pharmacokinetic studies identifying the presence or absence of soy protein in animal chow as the causative variable. Cyp3a11 expression in intestine and liver was determined to increase in a time dependent manner in mice switched to diets containing soybean meal compared with mice on diets without soybean meal. The repeated pharmacology experiments using the soybean meal free diet achieved plasma exposures that were maintained above the EC50 and showed efficacy and proof of concept for the target. This effect was further confirmed with marker CYP3A4 substrates in follow on mouse studies. The role of soy protein containing diets on CYP expression necessitates the inclusion of controlling rodent diet as a variable for preventing possible exposure differences between studies. SIGNIFICANCE STATEMENT: The presence of soybean meal protein in murine diet increased clearance and decreased oral exposure for select cytochrome 3A4 substrates. Related effects were also observed on select liver enzyme expression.