Validating Low‐Dose Iohexol as a Marker for Glomerular Filtration Rate by In Vitro and In Vivo Studies

Clearance of an intravenous iohexol dose of 3235 mg is used to assess glomerular filtration rate (GFR), although systematic assessment of its pharmacokinetic (PK) properties is incomplete. The objectives of the present investigations were (i) to assess potential interactions of iohexol with important drug transporters, and (ii) whether a 259 mg dose could replace the current standard dose. In vitro, we evaluated whether iohexol inhibits or is transported by renal transporters (hOAT1/3, hOCT2, and hMATE1/2K) or other transporters (hOATP1B1/3, hOCT1, and hMDR1) using cell-based and vesicle-based systems. In vivo, we conducted a clinical trial with 12 volunteers with the administration of single intravenous doses of 3235 mg ("reference") and 259 mg ("test") using a changeover design. Plasma and urine samples were collected up to 24 h postdose. We assessed the dose linearity of iohexol pharmacokinetics using the standard bioequivalence approach and conducted a population PK analysis to characterize its profile. Our in vitro findings indicate that iohexol is neither a substrate nor a significant inhibitor of the transporters, suggesting it is unlikely to participate in transporter-mediated drug-drug interactions in vivo. In the clinical trial, the test/reference ratio for plasma clearance, calculated as dose divided by the area under the plasma concentration-time curve, was 1.01 (90% confidence interval 0.968-1.05), confirming dose linearity. Population PK analysis further supported these results, showing no significant effect of dose on renal clearance and negligible nonrenal clearance of iohexol. Low-dose iohexol is a suitable marker for precise GFR measurement, even when coadministered with other drugs.