Toxicokinetic study of recombinant human heparin-binding epidermal growth factor-like growth factor (rhHB-EGF) in female Sprague Dawley rats.
OBJECTIVE
To determine the toxicity and pharmacokinetics of recombinant heparin-binding epidermal growth factor-like growth factor in female Sprague Dawley rats following intra-bladder and intravenous administration.


METHODS
rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 microg/kg. 125I-rhHB-EGF was administered on day 7 or 28 for pharmacokinetic analysis. Toxicity was assessed by general appearance and behavior, gross necropsy, blood chemistry and microscopic evaluation.


RESULTS
Plasma AUCss of [125I] rhHB-EGF equivalents following IB administration for 7 days were 4.28+/-2.29, 7.75+/-2.70, and 7.11+/-1.42 ng ml(-1) h(-1) at doses of 3, 10, and 30 microg/kg, respectively. Following IV administration, the AUCss on day 7 increased from 27.0+/-2.66 to 124+/-5.09 and 385.11+/-7.57 ng ml(-1) h(-1) with increasing the dose from 3 to 10 and 30 microg/kg. Similar AUCss data was obtained after 28 day administration. No toxicity was evident upon gross examination. Histologic examination revealed subacute inflammation and lymphocytic infiltration of the urinary bladder in animals from all groups dosed by the IB route.


CONCLUSIONS
Plasma and bladder concentrations of recombinant human [125I] rhHB-EGF equivalents were significantly lower following the IB route than following IV administration. Histologic tissue examination indicated no toxicity attributable to rhHB-EGF.
Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
Intira
I
Coowanitwong
Susan K
SK
Keay
Karthika
K
Natarajan
Tushar S
TS
Garimella
Clifford W
CW
Mason
David
D
Grkovic
Kenneth S
KS
Bauer
D000283:Administration, Intravesical; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D007457:Iodine Radioisotopes; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000633:toxicity; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins