Dose-dependent pharmacokinetics of 1-(2-deoxy-beta-D- ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine.
The dose-range pharmacokinetics of l-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C-aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from approximately 32 ml/min/kg at a dose of 15 mg/kg, to approximately 19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml(-1)) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% ( approximately 0.19 kg min ml(-1)) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from approximately 37 ml/min/kg to approximately 17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance. For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens.
Khalili
Panteha
P
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada T6G 2N8.
Naimi
Ebrahim
E
Sun
Wei Yan
WY
Knaus
Edward E
EE
Wiebe
Leonard I
LI
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000201:enzymology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003853:Deoxyribonucleosides; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012266:Ribose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000652:urine; D013997:Time Factors
C483745:1-(2-deoxyribofuranosyl)-2,4-difluoro-5-iodobenzene; D003853:Deoxyribonucleosides; D012266:Ribose; D007065:Idoxuridine