Building a Human Physiologically Based Pharmacokinetic Model for Aflatoxin B1 to Simulate Interactions with Drugs

Abstract

Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one’s daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence of chronic exposure, it is interesting to check for interactions with drugs taken concomitantly. A physiologically based pharmacokinetic (PBPK) model was developed based on the literature and in-house-generated in vitro data to characterise the pharmacokinetics (PK) of AFB1. The substrate file was used in different populations (Chinese, North European Caucasian and Black South African), provided by SimCYP® software (v21), to evaluate the impact of populations on AFB1 PK. The model’s performance was verified against published human in vivo PK parameters, with AUC ratios and Cmax ratios being within the 0.5–2.0-fold range. Effects on AFB1 PK were observed with commonly prescribed drugs in South Africa, leading to clearance ratios of 0.54 to 4.13. The simulations revealed that CYP3A4/CYP1A2 inducer/inhibitor drugs might have an impact on AFB1 metabolism, altering exposure to carcinogenic metabolites. AFB1 did not have effects on the PK of drugs at representative exposure concentrations. Therefore, chronic AFB1 exposure is unlikely to impact the PK of drugs taken concomitantly.

The Possible Role of Mycotoxins in the Pathogenesis of Endometrial Cancer

“…BMI and sudden changes in body weight may be important in the absorption of individual mycotoxins, age, and the accumulation of lipophilic molecules [ 20 ]. However, the rate of absorption of the mycotoxins is different: it is nearly complete in the case of AFs [ 21 ], and the lowest, around 4%, in the case of FB1 [ 22 ].…”

Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

“…The gender distribution was equally balanced, with an age range of 20–50 years. Subjects were exposed to a single dose of 30 ng AFB1 [ 15 ], which equals one-twentieth of the US maximum limit of 20 µg/kg AFs in a 30 g peanut butter sandwich [ 38 ], combined with a single dose of 600 mg EFV (labeled dose to treat HIV) [ 39 ]. Next, the same simulation was performed in an NEC population since commercially available human liver microsomes, employed in in vitro experiments as detailed in Section 5.2 , are from Caucasian subjects ( Figure 3 i).…”

“…The induction of CYP3A4 by EFV may potentially lead to interactions with AFB1 since it is partially metabolized by CYP3A4 [ 14 ]. Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ 15 ]. Drugs will rather have an impact on mycotoxin metabolism than vice versa, considering the magnitude of the ‘dose’ differences [ 15 ].…”

“…Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ 15 ]. Drugs will rather have an impact on mycotoxin metabolism than vice versa, considering the magnitude of the ‘dose’ differences [ 15 ]. To obtain insight into the possible impact of EFV on the pharmacokinetics (PK) of AFB1, PBPK simulations were performed where AFB1 and EFV were co-administered, and also in vitro experiments were carried out where AFB1 and EFV were co-incubated.…”