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A-158
2001
Pharmacokinetics of Carnosine, a Novel Oral Inotrope, in a Phase I Trial in Healthy Volunteers
Michael H. Wall, M.D.; Robert L. James, M.S.; Miyuki N. Shouse, M.S.; Pamela R. Roberts, M.D.; Richard C. Prielipp, M.D.
Anesthesiology, Wake Forest Univ. School of Medicine, Winston-Salem, North Carolina, United States
Introduction: Carnosine (CARN) is an endogenous dipeptide (beta-alanyl-histidine) found in muscle. It markedly increases contractility and improves relaxation in isolated rat hearts via effects on calcium sensitivity of the contractile proteins (1). It also increases intracellular release of calcium from the sarcoplasmic reticulum and increases the open state probability of the ryanodine receptor calcium release channel. We have recently shown that oral CARN increases cardiac output (CO) by 38% and stroke volume (SV) by 18% in healthy volunteers (2). In this report we describe the initial pharmacokinetic (PK) properties of oral CARN ingestion in humans.

Methods: Sixteen healthy volunteers ingested CARN (0.2 g/kg). Blood samples were drawn at baseline, 15, 30, 45, 60, 75, 90, 120, 150, and 180 min after consumption. Plasma levels were determined by HPLC (Waters, Boston, MA). The variability between subjects was so great that we were unable to perform standard PK analysis. Medians, minima, and maxima of 1) maximum concentration (MAX), 2) time to maximum concentration (MAX TIME), and 3) time to half-maximum concentration following the peak (HALF-MAX) were calculated using SAS software (SAS 8.1, SAS Institute, Cary, NC). HALF-MAX was estimated using linear regression. Clearance (CL) was calculated using non-compartmental methods, assuming 100% absorption and bioavailability. Raw data for the subjects are shown in the Figure. Mean plasma levels were analyzed by ANOVA and compared to baseline (time 0).

Results: Plasma CARN MAX was 430 nmol/mL (197,1116 nmol/mL) (median [minimum, maximum]), MAX TIME was 68 min (45, ≥180 min), HALF-MAX was 93 min (74, >180 min). CL was estimated to be 2.8 L/min (0.9, 11 L/min). See Figure. Mean CARN levels were significantly different from baseline at all time points (mean data not shown).Conclusions: Ours was the first phase I trial of carnosine effects on cardiac function and plasma levels in humans. PK modelling of oral carnosine appears challenging. CARN is an inotrope that is rapidly absorbed from the GI tract and rapidly eliminated from the blood. The rise in CARN plasma levels corresponds with the increases in CO and SV that were observed 30-80 min after ingestion (2). Further physiologic and PK studies of CARN in patients with congestive heart failure and critically ill patients are planned.

Supported in part by NIH MO1-RR07122, General Clinical Research Center, Wake Forest University School of Medicine

References:

1. Am J Physiol 1997;272:H462-468.

2. Crit Care Med 2000;28:A61

Anesthesiology 2001; 95:A158
Figure 1