A pharmacokinetic analysis of enterohepatic circulation of ursodeoxycholic acid, a drug with a high hepatic extraction but a small clearance.
Disposition profiles of ursodeoxycholic acid (UDCA) were studied by using a radioimmunoassay measuring serum UDCA after the single i.v. and oral 50 mg dose in five healthy subjects and in five patients with chronic liver disease. The healthy subjects also received single oral doses of 25, 100 and 300 mg of UDCA in a random order. The fasting pre-treatment UDCA concentrations were frequently higher in patients compared with the overall range of values in healthy subjects. The post-treatment concentrations were much higher in patients than in healthy subjects receiving the same i.v. and oral doses. A dose-dependent increase in AUC and Cmax after the oral UDCA doses was observed in normal subjects. The mean UDCA clearance in normal subjects was estimated to be much smaller than that expected and was apparently incompatible with the reported value for the hepatic extraction ratio of UDCA. This discrepancy was explained by an enterohepatic circulation which exists even in the fasting condition. The relationship between the hepatic extraction ratio and a substantial magnitude of enterohepatic circulation was formulated by using two newly defined concepts, hepatic extraction clearance and single path recirculating fraction.
Kubota
K
K
Division of Clinical Pharmacology, National Medical Center, Tokyo, Japan.
Yamaoka
K
K
Ishizaki
T
T
Makino
I
I
Shinozaki
K
K
Yamaguchi
A
A
Nakagawa
S
S
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D004764:Enterohepatic Circulation; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011863:Radioimmunoassay; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*
D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid