Serum can inhibit reversal of multidrug resistance by chemosensitisers

The Functional Role of P-Glycoprotein in the Blood–Brain Barrier

“…23,24 However, also a high affinity of a drug for Pgp in comparison with the coadministered reversal agent may result in a limited passage of the BBB, since most of the reversal agents act by competitive inhibition of Pgp. It is not clear which factors contribute to their diminished efficacy under in vivo conditions.…”

Strategies for reversing drug resistance

“…It was felt that high concentrations were needed because preclinical evidence suggested that serum protein binding would reduce the inhibitor's effectiveness (Lehnert et al, 1996). As a result of this strategy some agents, such as PSC-833, were administered at doses exceeding that needed to inhibit Pgp fully, as evidenced by use of surrogate markers .…”

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“…The uptake and entrapment of ivermectin by BMECs in the presence of serum (7), is at least 100-fold lower than the reported entrapment of cyclosporin A (27) and therefore, differences in inhibition of rhodamine 123 uptake by ivermectin and cyclosporin A in the presence of serum may reflect a combination of factors including differential protein binding and BMEC affinity for the two drugs. As pointed out by other researchers (28), the presence of serum in vivo and in vitro is an important variable in characterizing the inhibitory activity of some agents towards MDR1. primary …”

“…This observation was consistent with work in myeloma cell lines where Lehnert et al (28) demonstrated that cyclosporin A concentrations above those achievable in humans effectively inhibited MDR1 even in the presence of serum. However, Lehnert et al also observed that the actions other MDR1 inhibitors, amiodarone and trifluorperazine, were extremely sensitive over wide concentration ranges to the presence of serum (28). The uptake and entrapment of ivermectin by BMECs in the presence of serum (7), is at least 100-fold lower than the reported entrapment of cyclosporin A (27) and therefore, differences in inhibition of rhodamine 123 uptake by ivermectin and cyclosporin A in the presence of serum may reflect a combination of factors including differential protein binding and BMEC affinity for the two drugs.…”