Abstract
Recent cumulative evidence suggests the possibility of predicting thein vivo metabolic clearance and/or hepatic availability (Fh) from in vitro metabolism data under linear conditions. Under nonlinear conditions, however, it is essential to consider the rate constant for the absorption (ka) for predicting Fh after oral administration, because the time profiles for the portal vein concentration depends on ka. In our study, we numerically solved the dispersion model under nonlinear conditions to propose a method to predict Fhafter oral administration by taking ka into consideration. As a model compound, (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-l-tartrate monohydrate (YM796) was used. After oral administration, we found that the dose-normalized AUC (AUCoral/dose) was markedly increased in rats from 5.0×10−6 to 33×10−6hr/ml·kg as the dose increased from 1 to 10 mg/kg, whereas the same value was relatively constant in dogs (87.7×10−6 to 105×10−6 hr/ml·kg at 1 to 10 mg/kg) and in humans (1260×10−6 to 1768×10−6 hr/ml·kg at 5 to 60 mg/body). Kinetic analysis indicated that AUCoral could be accurately predicted at each dose if ka value was assumed as 0.07 min−1 for all animal species examined in our study. These results suggest that it is possible to predict Fh even if the metabolism is composed of non-linear process by considering the absorption rate into the portal vein.
Footnotes
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Send reprint requests to: Dr.Yuichi Sugiyama, Ph.D., Faculty of Pharmaceutical Sciences, The University of Tokyo, 7–3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan.
- Abbreviations:
- AUCoral
- area under the plasma concentration-time curve after oral administration
- CLh
- hepatic clearance
- Clint
- overall intrinsic metabolic clearance (intrinsic hepatic clearance)
- CLns
- intrinsic metabolic clearance for the nonsaturable component
- CLoral
- oral clearance (= dose/AUCoral)
- CLr
- renal clearance
- DN
- dispersion number
- Fa
- fraction absorbed from the intestinal tract
- Fg
- gastrointestinal availability
- Fh
- hepatic availability
- fb
- unbound fraction in blood
- fp
- unbound fraction in plasma
- GE
- gastric emptying
- Km,i
- Michaelis-Menten constant for the i-th component of the metabolic reaction
- Qh
- hepatic blood flow rate
- RB
- blood-to-plasma concentration ratio
- Vmax,i
- maximum metabolic rate for the i-th component of the metabolic reaction
- Received April 15, 1997.
- Accepted March 11, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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