Vol.53 No.S-1 July 2005

Effect of probenecid on pharmacokinetics of doripenem in healthy male volunteers

Kohya Shiba¹⁾ and Mitsuyoshi Nakashima²⁾

¹⁾Department of Internal Medicine (Department of Infection Control), Jikei University,
3-25-8 Nishishinbashi, Minato-ku, Tokyo, Japan
²⁾Hamamatsu Institute of Clinical Pharmacology & Therapeutics

Abstract

To determine the effects of probenecid on the renal excretion of doripenem (DRPM), a new carbapenem antibiotic for injection, we conducted an open-label, crossover (two-drug, two-period), single-dose study of DRPM in eight healthy male volunteers. DRPM was administered intravenously at a dose of 250 mg with or without probenecid. Concentrations in plasma and urine were determined to evaluate differences in pharmacokinetic profiles between two groups-one in which only DRPM was administered (DRPM group) and one in which DRPM was administered in combination with probenecid (DRPM/probenecid group).
Pharmacokinetic parameters in the DRPM group were as follows: Cmax, 15.7±2.8 μg/mL; AUC, 17.10±2.56 μg · h/mL; and half-life (t_1/2), 0.94±0.16 h. Pharmacokinetic parameters in the DRPM/probenecid group were as follows: Cmax, 18.1±1.4 μg/mL; AUC, 29.86±2.10 μg · h/mL; and t_1/2, 1.44±0.11 h. The DRPM/probenecid group showed significant increases in Cmax and AUC (p=0.0091, p<0.0001), significant prolongation of t_1/2 (p=0.0002), and a significant decrease in the following parameters: systemic clearance, 8.41±0.58 L/h versus 14.91±2.22 L/h in the DRPM group (p<0.0001); renal clearance, 5.52±0.71 L/h versus 12.00±2.21 L/h in the DRPM group (p=0.0001); and cumulative urinary excretion (0-12h), 65.8±8.6% versus 80.4±8.0% in the DRPM group (p=0.0017).
These significant pharmacokinetic differences suggest that DRPM is excreted both by glomerular filtration and tubular secretion.

Key word

doripenem, probenecid, pharmacokinetic, healthy volunteer

Received

January 11, 2005

Accepted

March 15, 2005

Jpn. J. Chemother. 53 (S-1): 136-142, 2005