The impact of plasma protein binding on the renal transport of organic anions.
Drugs and xenobiotics bind to plasma proteins with varying degrees of affinity, and the amount of binding has a direct effect on free drug concentration and subsequent pharmacokinetics. Multiple active and facilitative transport systems regulate the excretion of anionic compounds from the blood in excretory and barrier tissues. Assumptions are made about in vivo substrate affinity and route of elimination based on data from plasma protein-free in vitro assays, particularly following expression of cloned transporters. Ochratoxin A (OTA), a fungal mycotoxin, is a high-affinity substrate for several renal secretory organic anion transporters (OATs), and literature suggests that this elimination pathway is the route of entry leading to proximal tubule-targeted toxicity. However, OTA is known to bind to several plasma proteins with a high affinity, particularly serum albumin, which may impact elimination. In this study, we have systematically examined the handling of OTA and other organic anions, estrone sulfate (ES) and methotrexate (MTX), by OATs in the presence of serum albumin. Increasing concentrations of albumin markedly reduced uptake of OTA by both Xenopus laevis oocytes expressing OATs 1, 3, and 4 and organic anion-transporting polypeptide 1. For all transporters tested, virtually all mediated OTA uptake was eliminated by an albumin concentration equivalent to 10% of that present in the blood plasma. Thus, OTA uptake is dependent on the free substrate concentration and severely limited by binding to human serum albumin. MTX and ES uptake were likewise dependent on free concentration.
Bow
Daniel A J
DA
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Mail Drop F1-03, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
Perry
Jennifer L
JL
Simon
John D
JD
Pritchard
John B
JB
D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001798:Blood Proteins / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D004970:Estrone / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D008727:Methotrexate / Q000378:metabolism; D009793:Ochratoxins / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D011485:Protein Binding; D018075:RNA, Complementary / Q000096:biosynthesis; D012709:Serum Albumin / Q000378:metabolism; D014982:Xenopus laevis
D001798:Blood Proteins; D005493:Folic Acid Antagonists; D009793:Ochratoxins; D027361:Organic Anion Transporters; D018075:RNA, Complementary; D012709:Serum Albumin; C025589:ochratoxin A; D004970:Estrone; D008727:Methotrexate