Effect of the anticoagulant ethylenediamine tetra-acetic acid (EDTA) on the estimation of pharmacokinetic parameters: A case study with tigecycline and ciprofloxacin.
Tigecycline and ciprofloxacin were employed as the model compounds to study the effect of the anticoagulant ethylenediamine tetra-acetic acid (EDTA), which is used during plasma sample preparations, on the determination of pharmacokinetic parameters. The pharmacokinetic parameters were determined in rats following intravenous infusion with blood samples collected in serum separators, with either EDTA- or heparin-coated tubes. The blood-to-plasma (B:P) partition ratio and plasma protein binding were determined in vitro in rat or human blood collected in either EDTA- or heparin-coated tubes. Drug concentrations were quantified by liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS) analysis. In tigecycline-treated rats drug concentrations were twofold lower in EDTA plasma, leading to a twofold lower area under plasma concentration-time curve (AUC) and twofold higher plasma clearance values as compared with those obtained from heparin plasma. No differences were noted in the pharmacokinetic parameters obtained from heparin-treated plasma versus serum. The B:P partition ratio and unbound fraction for tigecycline were significantly higher in EDTA-treated blood. When normalized to the B:P partition ratios, the tigecycline blood clearance values were identical between samples collected in EDTA- or heparin-coated tubes. Similar but smaller differences were observed for ciprofloxacin. It was concluded that EDTA might compete with tigecycline and ciprofloxacin for chelating metal ions and thus affect drug partition between blood and plasma compartments, leading to inaccurate measurement of pharmacokinetic parameters in plasma.
Chen
Q
Q
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, NJ 07065, USA. qing_chen@merck.com
Tung
E C
EC
Ciccotto
S L
SL
Strauss
J R
JR
Ortiga
R
R
Ramsay
K A
KA
Tang
W
W
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D000925:Anticoagulants / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000493:pharmacokinetics*; D004492:Edetic Acid / Q000494:pharmacology*; D008297:Male; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000078304:Tigecycline; D013997:Time Factors
D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D002939:Ciprofloxacin; D000078304:Tigecycline; D004492:Edetic Acid; D008911:Minocycline