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Pharmacokinetic and pharmacodynamic study of a novel chimeric natriuretic peptide, CD-NP, in the normal dog

Background

CD-NP is a novel Mayo-designed cGMP-activating chimeric natriuretic peptide (NP) that consists of the 22-amino-acid (AA) residues of C-type natriuretic peptide (CNP) and the 15-AA C-terminus of Dendroaspis NP [1]. The rationale for its design was to transform CNP, a cardioprotective peptide with limited renal actions, into a chimeric peptide with both cardiovascular and renal effects. Previous studies from our laboratory have demonstrated that CD-NP was natriuretic, diuretic, cardiac-unloading, and renin-suppressing [1]. In this investigation, we studied the pharmacokinetics (PK) of CD-NP for the first time and further evaluated its pharmacodynamic profile in vivo.

Materials and methods

CD-NP 50 ng/kg/min was administered as a continuous i.v. infusion for 75 minutes to ten normal anesthetized dogs. Four 30-min clearances were performed: pre-infusion, 30-min of infusion (I), 60-min I, and post-I. Glomerular filtration rate (GFR) was measured by inulin clearance. Comparisons of cardiorenal and neurohormonal parameters were made within group versus pre-I (mean ± S.E.M., P < 0.05*, <0.01). For PK study (n = 4), blood was collected at baseline, at 25th, 30th, 45th, 60th, and 75th min during infusion (I); and at 1st, 2nd, 4th, 6th, 10th, 20th, 30th, 45th, 60th min post-I. An established CNP radioimmunoassay was employed to detect plasma CNP immunoreactivity, as an estimate for CD-NP levels. Non-compartmental PK analysis was performed (WinNonlin version 5.2, Pharsight Corporation, CA).

Results

The elimination half-life of CD-NP was 18.4 ± 1.4 min, volume of distribution (VD) based on the terminal phase was 3.1 ± 1 L/kg, steady-state VD was 1.6 ± 0.5 L/kg and total body clearance was 111 ± 32 ml/min/kg. The maximum observed concentration was 1183 ± 388 pg/ml and time to maximum observed concentration was 48.8 ± 11.3 min. CD-NP increased urine flow (0.23 ± .06 to 1.81 ± .26 ml/min), urinary Na+ excretion (18.6 ± 3.7 to 237 ± 26 meq/min), and GFR (37 ± 2 to 53 ± 4 ml/min). These renal actions were associated with an increase in net renal cGMP generation (705 ± 143 to 4194 ± 770 pmol/min). Proximal and distal fractional reabsorption of Na+ decreased (75 ± 2 to 57 ± 3%; 98 ± .2 to 92 ± 1%, respectively). Urinary K+ excretion increased (26.4 ± 3.7 to 64.1 ± 4.3 meq/min). Decreases in pulmonary arterial pressure (11.7 ± .6 to 10.3 ± .4* mmHg), pulmonary capillary wedge pressure (5.7 ± .7 to 3.2 ± .7 mmHg), and right atrial pressure (1.9 ± .4 to 0.9 ± .5 mmHg) were observed with no significant change in systemic blood pressure. At the end of CD-NP infusion, there was no significant change in heart rate (120 ± 8 vs 110 ± 8 bpm pre-I) or the QTc interval (310 ± 9 vs 309 ± 9 msec pre-I). An increase in hematocrit (36 ± .9 to 38 ± .6%) was noted.

Conclusion

CD-NP exhibits a favorable pharmacologic profile in normal dogs without induction of systemic hypotension. Its therapeutic potential as a novel drug for the treatment of heart failure and other cardiorenal disease states warrants further investigation.

References

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Acknowledgements

Supported by the National Institutes of Health (HL36634; PO1 HL76611 and HL80732), the Mayo Foundation, and the Canadian Institutes of Health Research.

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Correspondence to Candace YW Lee.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Lee, C.Y., Boerrigter, G., Harty, G.J. et al. Pharmacokinetic and pharmacodynamic study of a novel chimeric natriuretic peptide, CD-NP, in the normal dog. BMC Pharmacol 7, P38 (2007). https://doi.org/10.1186/1471-2210-7-S1-P38

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Keywords

  • Inulin
  • Pulmonary Capillary Wedge Pressure
  • Renal Action
  • Chimeric Peptide
  • Fractional Reabsorption