Determination of in vivo hepatic extraction ratio from in vitro metabolism by rat hepatocytes.
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.
Research Department, Ciba-Geigy Corp., Summit, NJ 07901.
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Singh
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Tripp
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Dunton
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Douglas
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Rakhit
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D011433:Propranolol / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D014150:Antipsychotic Agents; D001798:Blood Proteins; D011433:Propranolol; D003024:Clozapine; C061853:batelapine; D000983:Antipyrine