Allosteric Modification of Oxygen Delivery by Hemoglobin

Abstract

Hemoglobin affinity for oxygen is altered by pH, temperature, and high altitude, making oxygen more readily available to the tissues. RSR13 (Allos Therapeutics, Denver, CO), an analog of the drugs clofibrate and bezofibrate, causes a dose-dependent, rightward shift of the oxygen dissociation curve in animals and humans. We tested the safety, pharmacodynamic, and pharmacokinetics of RSR13, an allosteric modifier of hemoglobin, in patients having general surgery in a prospective, randomized, double-blinded, placebo-controlled, dose-escalation clinical trial. After the induction of general anesthesia with endotracheal intubation, 26 patients who consented were randomly assigned to receive an infusion of RSR13 or placebo (2:1) in an ascending dose scheme. Doses studied were 10, 20, 30, 40, 50, 60, 75, and 100 mg/kg infused for 30–60 minutes. Samples were taken for determination of RSR13 concentration in plasma, red blood cells, and urine, as well as for determination of the p50 in blood by using three-point tonometry at frequent intervals after the infusion of the study drug. The RSR13 administration resulted in a dose-dependent rightward shift of the oxygen dissociation curve, with the target p50 shift of 10 mm Hg achieved at the 75- and 100-mg/kg doses. No differences were seen between RSR13 and placebo groups in laboratory or hemodynamic findings, with the exception of a transient, limited increase in serum creatinine in 3 patients who received RSR13. These increases peaked at 48 h (2.2, 3.5, and 4.5 mg/dL respectively), were not associated with oliguria, did not require treatment, and did not prolong hospitalization in any patient. The reasons for the unexplained increases in serum creatinine were not evident, but potentially included surgery itself (nephrectomy), patient condition, or the concomitant administration of renally cleared medications or drugs that affect renal blood flow.