Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog

Abstract

Hydroxypropyl-β-cyclodextrin (HPβCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPβCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPβCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPβCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.

Keywords: Anesthetized dog; Blood pressure; CD; CI; CO; CV; Complexation agent; DBP; FDA; Food and Drug Administration; GFR; GLP; Good Laboratory Practice; HPβCD; HR; Heart rate; Hemodynamics; Hydroxypropyl-β-cyclodextrin; IC; IU; LVEDP; LVP; MBP; NOAEL; NS; OECD; Organization for Economic Cooperation and Development; PAP; PCWP; RBF; RRES; Renal blood flow; Renal resistance; Renal toxicity; SBEγCD; SBP; SV; Safety pharmacology; TPRES; cardiac output; cardiovascular; confidence interval; cyclodextrin; diastolic blood pressure; glomerular filtration rate; hERG; heart rate; human ether-a-go-go related gene; hydroxypropyl-β-cyclodextrin; inhibitory concentration; international unit; left ventricular end diastolic pressure; left ventricular pressure; mean blood pressure; no observed adverse effect level; not significant; pulmonary arterial pressure; pulmonary capillary wedge pressure; renal arteriolar resistance; renal blood flow velocity; stroke volume; sulfobutylether-γ-cyclodextrin; systolic blood pressure; total peripheral resistance; w/v; weight/volume.