Comparison between the results of the in vivo study and the in silico simulations determined the quality and reliability of the in silico predictions and demonstrate the simulation of dose dependent absorption. In contrast to previous simulation work for the non-linear dose dependence of interaction with intestinal transporters or enterocyte metabolism, optimized Km and Vmax values were required to reproduce the clinically observed non-linear dose dependence. The model developed may be useful in the prediction of absorption of other P-gp substrates including pharmacodynamic consequences.
Summary
After the intravenous administration of nitrofurantoin sodium to dogs at nitrofurantoin doses of 1·5–24·0 mg/kg, a substantial amount of nitrofurantoin is excreted in bile. The bile to blood drug ratios were about 200. A marked hydrocholeretic effect which correlated directly with the amount of nitrofurantoin administered was also observed.
The excretion of nitrofurantoin in bile and the hydrocholeretic effect were linear with the dose of drug over the range 1·5–12·0 mg/kg. Maximum increases in hepatic bile flows were usually from 5–10 ml/0·5 h, while average control bile flow was 1·6 ml ± s.d. 0·6/0·5 hours. The lowest dose at which the hydrocholeretic effect was still detectable was 0·09 mg/kg.
Apparent saturation of the biliary excretion system for nitrofurantoin and the hydrocholeretic mechanism occurred after a dose of 24·0 mg/kg. Saturation of the urinary system for nitrofurantoin excretion was noted after a dose of 6·0 mg/kg.
Biliary nitrofurantoin recoveries ranged from 16·5% ± s.d. 4·2 to 22·6% ± s.d. 4·7 for the 6 h period after doses of 1·5, 30, and 6·0 mg/kg. Urinary nitrofurantoin recoveries for the same interval ranged from 24·1% ± s.d. 6·6 to 36·2% ± s.d. 8·3.
In comparison to values obtained in normal dogs, only about one‐tenth of the drug excretion in bile and about one‐fifth of the hydrocholeretic effect were obtained after intravenous drug administration to dogs with hepatic impairment induced by CCl4.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.