Premium
DOSE‐INDEPENDENT PHARMACOKINETICS OF THE CARDIOPROTECTIVE AGENT DEXRAZOXANE IN DOGS
Author(s) -
Baldwin John R.,
Lewis Richard C.,
Phillips Barbara A.,
Overmyer Stephen K.,
Hatfield Naomi Z.,
Narang Prem K.
Publication year - 1996
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199608)17:6<541::aid-bdd975>3.0.co;2-5
Subject(s) - pharmacokinetics , dexrazoxane , chemistry , volume of distribution , beagle , urine , renal function , pharmacology , distribution (mathematics) , blood proteins , chromatography , medicine , anthracycline , biochemistry , mathematical analysis , mathematics , cancer , breast cancer
A randomized, four‐way cross‐over design was used to assess the disposition of the cardioprotective agent, dexrazoxane, in four male beagle dogs following single I.V. administration of 10, 25, 50, and 100 mg kg −1 doses. Parent drug was quantified in plasma and urine with a validated high‐pressure liquid chromatographic–electrochemical assay. A two‐compartment open model adequately described the dexrazoxane plasma concentration versus time data. The terminal half‐life ranged between 1·1 and 1·3 h and the apparent steady‐state distribution volume was 0·67 L kg −1 . The systemic clearance (CL) ranged from 10.3 to 11·5 mL min −1 kg −1 , while estimates of renal clearance approximated the glomerular filtration rate (GFR ≈3·2–4·9 mL min −1 kg −1 ). Over the dose range evaluated, CL was dose independent (ANOVA, p =0·33), while concentration at the end of infusion ( C end ) and the area under the concentration versus time curve (AUC) were directly proportional to the dose ( r >0·999). The blood cell to plasma partitioning ratio was ≈0·517 and drug was essentially unbound to plasma proteins ( f u ≈0·95). Dexrazoxane appeared to be subject to low organ extraction, since the hepatic and renal drug extraction ratios were on the order of 0·228±0·054 and 0·184±0·024, respectively. These results suggest a relatively small drug distribution space (approximately equal to total‐body water) and low tissue and plasma protein binding. In light of the low plasma protein binding and extraction ratio exhibited by dexrazoxane, metabolic capacity and renal function would appear to be the predominant variables affecting the CL of this drug. The constancy of the half‐life, CL, and V ss with increasing dose indicates dose‐independent disposition for dexrazoxane. Thus a linear increase in the systemic exposure can be predicted over this dose range.