Abstract
Sodium tungstate has been found to correct hyperglycemia in insulin- and noninsulin-dependent models of diabetes when administered in drinking fluid with a low degree of toxicity; thus, it provides a potential treatment for diabetes. In the present report, pharmacokinetic studies with sodium tungstate were carried out in the Sprague-Dawley rat and beagle dog. This drug was administered either i.v. (8.97 mg/kg in rat; 25 and 50 mg/kg in dog) or orally in the form of solution (35.9 and 107.7 mg/kg in rat; 25 and 50 mg/kg in dog). Tungsten was quantified using an inductively coupled plasma method. Pharmacokinetic parameters were estimated using a population approach. Sodium tungstate followed first order kinetics, and plasma concentration-versus-time data were adequately described by a two-compartment model. In rat, bioavailability was high (92%), whereas it was lower in dog (approximately 65%). The total volume of distribution expressed by unit of body weight was much higher when the animal was smaller (0.46 l/kg in rat versus 0.23 l/kg in dog). The total body clearance normalized by weight, 0.19 l/h/kg in rat versus 0.043 l/h/kg in dog, changed as for the volume of distribution. The elimination half-life was two times higher in dog (approximately 4 h) than in rat (approximately 1.7 h). In the range of 35.9 to 107.7 mg/kg after oral administration in rat and 25 to 50 mg/kg after oral and i.v. administration in dog, tungsten plasma concentrations increased in proportion to dose.
Footnotes
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Send reprint requests to: Dr. Françoise Bressolle, Ph.D., Laboratoire de Pharmacocinétique Clinique, Facultéde Pharmacie, 34060 Montpellier Cedex 2, France. E-mail:Fbressolle{at}AOL.com
- Abbreviations:
- t1/2elim
- elimination half-life
- RBC
- red blood cell
- E step
- expectation step
- M step
- maximization step
- CL
- total clearance
- V
- initial volume of distribution
- Vd
- steady-state volume of distribution
- k21
- k12, transfer rate constants
- kel
- elimination rate constant
- ka
- absorption rate constant
- t1/2ka
- absorption half-life
- F
- bioavailability
- tlag
- lag time
- AUC
- area under the plasma concentration-time curve
- Cmax
- maximum plasma concentration
- tmax
- time ofCmax
- Cexp
- expected concentrations
- Cobs
- observed concentrations
- SCPE
- standardized concentrations prediction error
- CV
- coefficient of variation
- Received January 24, 2000.
- Accepted May 5, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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