title: HPLC measurement, blood distribution, and pharmacokinetics of oral clotrimazole, potentially useful antisickling agent.
abstract: Clotrimazole (CLT) has recently been shown to be a potent and specific inhibitor of the Ca(2+)-activated K+ channel and to thereby prevent K+ loss and cellular dehydration of sickled erythrocytes. This evidence suggests that oral CLT may be a useful new therapy for sickle cell disease. Here, we describe the development of an HPLC assay to measure CLT, a method we used to study the pharmacokinetics and transport of CLT in normal volunteers. The assay's linear range extended to 10 mumol/L; the detection limit was 0.1 mumol/L, analytical recovery 97.7%, and run-to-run imprecision (CV) < 4.7%. In unaffected subjects, CLT concentration peaked within 6 h of oral administration and returned to close to baseline by 24 h. High-density lipoproteins appear to be the main carriers of this drug in both normo- and hypertriglyceridemic plasma. We conclude that the method described here is ideally suited for therapeutic monitoring of CLT concentrations.
authors.affiliation: Department of Laboratory Medicine, Children's Hospital, Boston, MA 02115.
authors.forename: N
authors.initials: N
authors.lastname: Rifai
authors.forename: M
authors.initials: M
authors.lastname: Sakamoto
authors.forename: T
authors.initials: T
authors.lastname: Law
authors.forename: O
authors.initials: O
authors.lastname: Platt
authors.forename: M
authors.initials: M
authors.lastname: Mikati
authors.forename: C C
authors.initials: CC
authors.lastname: Armsby
authors.forename: C
authors.initials: C
authors.lastname: Brugnara
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid / Q000706:statistics & numerical data; D003022:Clotrimazole / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000097:blood
chemical_list: D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides; D000251:Adenosine Triphosphatases; C029321:calcium potassium ATPase; D003022:Clotrimazole