Therapeutic Doses of Eltrombopag do not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model

Abstract

The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review

“…Cefuroxime also showed a great variation in protein binding in critically ill patients (0.25%–72.64%) ( van Raaij et al, 2020 ). As mentioned earlier, patients on hemodialysis showed lower protein binding (8%) for ceftriaxone compared to healthy volunteers (protein binding 90%–95%) ( Stoeckel et al, 1984 ; Matzke et al, 2000b ; Neves et al, 2018 ; Herrera-Hidalgo et al, 2020 ). This was also seen for cefepime in patients on continuous venovenous hemofiltration and continuous venovenous hemodialysis.…”

“…This was confirmed for cefazolin, which was bound for mean 72.3% in cirrhotic patients ( Ohashi et al, 1986 ). Also for ceftriaxone protein binding was lower (83.9% vs. 90%–93% in healthy volunteers) ( Stoeckel et al, 1984 ; Mimoz et al, 2000 ; Neves et al, 2018 ; Herrera-Hidalgo et al, 2020 ) as well as for cefpiramide (89.6 vs. 98.1 in healthy volunteers) ( Demotes-Mainard et al, 1991 ). For cefalothin there was not a significant difference in protein binding between patients with cirrhosis (73.4%) and controls (75.9%) ( Ohashi et al, 1986 ).…”

“…For example, protein binding for cefoxitin was mean 41.5% in patients on hemodialysis ( Garcia et al, 1979a ), compared healthy volunteers (mean 52%) ( Carver et al, 1989 ). The same applies to ceftriaxone [mean 43% for dialysis patients ( Matzke et al, 2000b ) and 90%–93% for healthy volunteers ( Mimoz et al, 2000 ; Neves et al, 2018 ; Herrera-Hidalgo et al, 2020 )].…”

“…Even for a specific cephalosporin, the protein binding differs between different categories of patients and even within the categories there was a considerable amount of variability. For ceftriaxone, for example, a group of eight patients on hemodialysis displayed a mean protein binding of 43% ( Matzke et al, 2000b ), which was considerably lower compared to healthy volunteers (mean/median 90%–95%) ( Stoeckel et al, 1984 ; Neves et al, 2018 ; Herrera-Hidalgo et al, 2020 ). However, even within the group of dialysis patients the protein binding ranged approximately from 13% to 73% ( Matzke et al, 2000b ).…”

Epithelial lining fluid concentrations of ceftriaxone in children with community‐acquired pneumonia

“…Previous studies have shown that different efflux transporters are expressed in alveolar epithelial cells of human, including P-glycoprotein, multidrug-resistance-associated protein 1 (MRP1), and breast cancer resistance protein. 17 Also, ceftriaxone is a substrate of multidrug-resistance-associated protein 2 and breast cancer resistance protein 18 and can block the P-glycoprotein function. 19 These factors may be related to the high penetration and require further study.…”