RT Journal Article
SR Electronic
T1 Determination of in vivo hepatic extraction ratio from in vitro metabolism by rat hepatocytes.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 990
OP 996
VO 19
IS 5
A1 K Singh
A1 S L Tripp
A1 A W Dunton
A1 F L Douglas
A1 A Rakhit
YR 1991
UL http://dmd.aspetjournals.org/content/19/5/990.abstract
AB Using isolated rat hepatocytes, the in vitro intrinsic hepatic clearance of three drugs, namely, antipyrine (AP), propranolol (P), and CGS 13429 was determined. The hepatic extraction ratios of AP, P, and CGS 13429 were then calculated to be 0.10, 0.90, and 0.88, respectively. To determine the in vivo hepatic extraction ratio in the rat, AP, P, or CGS 13429 was infused separately at a rate of 40, 20, and 20 micrograms/min.kg, via jugular and hepatic portal veins. The steady state plasma levels of AP, P, and CGS 13429 were 5.30 +/- 0.33 micrograms/ml, 608 +/- 76 and 380 +/- 46 ng/ml after jugular vein (iv) infusions, and 4.96 +/- 0.46 micrograms/ml, 162 +/- 26, and 148 +/- 23 ng/ml after hepatic portal vein (hpv) infusions, respectively. The blood to plasma ratios of AP, P, and CGS 13429 were 1.0, 0.78, and 1.0, respectively. The in vivo hepatic extraction ratio, calculated as (Css,iv--Css,hpv)/Css,iv from steady state blood levels following iv and hpv infusions for AP, P, and CGS 13429, were 0.065, 0.73, and 0.61, respectively. These results suggest that in vitro metabolism studies by hepatocytes may have potential application, during drug discovery, to distinguish drugs of low and high metabolic hepatic extraction ratio in vivo.