Toxicokinetic Study of Recombinant Human Heparin-Binding Epidermal Growth Factor-Like Growth Factor (rhHB-EGF) in Female Sprague Dawley Rats |
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Authors: | Intira Coowanitwong Susan K Keay Karthika Natarajan Tushar S Garimella Clifford W Mason David Grkovic Kenneth S Bauer |
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Institution: | (1) Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA;(2) Veterans Administration Medical Center, Baltimore, Maryland, USA;(3) Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA;(4) University of Maryland School of Pharmacy, Allied Health Building—Suite 540, 100 Penn Street, Baltimore, Maryland 21201, USA |
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Abstract: | Purpose 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.
Materials and Methods rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 μg/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 μg/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 μg/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. |
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Keywords: | HB-EGF interstitial cystitis intrabladder instillation intravenous administration pharmacokinetics NONMEM toxicity toxicokinetics |
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