A Physiologically-Based Pharmacokinetic (PBPK) Model Network for the Prediction of CYP1A2 and CYP2C19 Drug-Drug-Gene Interactions with Fluvoxamine, Omeprazole, S-mephenytoin, Moclobemide, Tizanidine, Mexiletine, Ethinylestradiol, and Caffeine.

Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug exposure. However, there are only few verified, freely accessible, modifiable, and comprehensive drug-drug interaction (DDI) PBPK models. We developed a qualified whole-body PBPK DDI network for cytochrome P450 (CYP) CYP2C19 and CYP1A2 interactions. Template PBPK models were developed for interactions between fluvoxamine, S-mephenytoin, moclobemide, omeprazole, mexiletine, tizanidine, and ethinylestradiol as the perpetrators or victims. Predicted concentration-time profiles accurately described a validation dataset, including data from patients with genetic polymorphisms, demonstrating that the models characterized the CYP2C19 and CYP1A2 network over the whole range of DDI studies investigated. The models are provided on GitHub (GitHub Inc., San Francisco, CA, USA), expanding the library of publicly available qualified whole-body PBPK models for DDI predictions, and they are thereby available to support potential recommendations for dose adaptations, support labeling, inform the design of clinical DDI trials, and potentially waive those.

Effect of interleukin-2 on intestinal P-glycoprotein expression and functionality in mice.

P-glycoprotein (Pgp), an active drug transporter expressed in enterocytes, can reduce intestinal absorption of drugs. Until now, interleukin-2 (IL2) has been reported as a Pgp modulator only in vitro. The present study examines the effects in vivo of IL2 after chronic treatment on intestinal Pgp protein expression and activity. This work also describes the effects of IL2 on the oral bioavailability of a Pgp substrate (digoxin) and of a Pgp/CYP3A cosubstrate (saquinavir). Human recombinant interleukin-2 (rIL2), administered to mice at 9 million international units/kg by intraperitoneal route twice daily for 4 days, led to a decrease in intestinal Pgp protein expression evaluated by Western blot with C219 antibody. In an in vitro everted gut sac model, rIL2 pretreatment decreased the Pgp-mediated transport of rhodamine 123 across mouse intestine by 37%. Moreover, rIL2 pretreatment markedly raised the area under the curve of orally administered digoxin from 3.5 +/- 0.5 to 9.7 +/- 1.5 mg min l(-1) as a consequence of the reduction in intestinal Pgp activity. rIL2 treatment increased saquinavir bioavailability from 2.5 to 4.5%, showing that first-pass metabolism is not affected and that Pgp by itself has only a moderate effect on saquinavir oral bioavailability. In conclusion, rIL2 pretreatment reduces intestinal Pgp protein expression and activity in mice. However, the effect of such a treatment on drug bioavailability depends on the extent of their metabolism by CYP3A.