**Author details**

mechanisms underlying downregulation of drug-metabolizing enzyme and transporter levels by cytokines are not fully defined but lower gene and protein expressions have been reported for some nuclear receptors involved in regulation of CYPs and transporters including preg‐ nane X receptor (PXR), constitutive androstane receptor (CAR), and farnesoid X activated receptor (FXR) [83, 84]. Although in vitro systems (e.g., microsomes and hepatocytes) are routinely employed to predict in vivo DDIs of small molecules [85], the use of in vitro systems to predict in vivo interactions between small-molecule drugs and therapeutic proteins is still in development. Most of the problems are caused by poor correlation and extrapolation

Influencing the levels of expression of P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1), can also contribute to DDIs. Several studies have shown that intestinal P-gp was inversely correlated with the inflammatory disease activity. Cytokinemediated downregulation of P-gp in inflamed intestine of ulcerative colitis (UC) patients was presumably dependent on disease activity, with a possible contribution from IL-8 [86]. Presence of P-gp in the membranes of blood-brain-barrier (BBB) restricts passage of drug molecules into the brain. Some studies show that activity of P-gp was downregulated after short-term exposure to inflammatory mediators, whereas its activity was upregulated

Modulation of activity of CYP enzymes by monoclonal antibodies, through interactions with ILs, can enter into interactions with drugs, which are metabolized by CYPs. Clinical studies have shown that IL-6 inhibits function of CYP1A2, 2C9, 2C19, and CYP3A4 and the function is normalized by anti-IL-6 receptor antibody – tocilizumab [89]. When patients taking drugs with a narrow therapeutic index that are metabolized by these CYP enzymes, for example, atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, cyclosporine, or benzodiazepines, blood levels of these drugs should be monitored and clinicians should be alert for possible interactions. It should be taken into account that monoclonal antibodies have long elimination half-life and the effect on CYP enzymes activity may continue after treatment

Pharmacodynamic (PD) interactions using monoclonal antibodies are also possible. The basic mechanisms that are involved include reduction in target number or target-bearing cell number, thus affecting receptor-mediated clearance [90]. The use of pharmacodynamic interactions to improve the pharmacological effect of monoclonal antibodies is growing [91, 92]. In nonhuman primates, paclitaxel in combination with trastuzumab resulted in a 1.5-fold increase in trastuzumab serum concentration [93]. Similarly, paclitaxel enhances the thera‐ peutic benefit of cetuximab, possibly through inhibition of angiogenesis and the induction of apoptosis [94]. Pharmacodynamic interactions have also been reported in other clinical and preclinical experiments [95-97]. A combination of cetuximab (mAb-targeting epidermal growth factor receptor, EGRF) with either gefitinib or erlotinib (EGRF tyrosine kinase inhibi‐ tors) was used to maximize EGRF signaling inhibition [98]. Synergism between these drugs has been reported in vivo in athymic nude mice and in vitro across a variety of human cancer cell models. Synergistic antitumor activity has been reported between a taxane compound

between in vitro and in vivo results.

276 Immunopathology and Immunomodulation

following more prolonged exposure [87, 88].

(BMS-275183) and cetuximab using athymic nude mice [99].

for several weeks.

Kaloyan Georgiev\* and Marieta Georgieva

\*Address all correspondence to: kalgeorgiev@hotmail.com

Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University Varna, Varna, Bulgaria

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