Oxygen dependence of omeprazole clearance and sulfone and sulfide metabolite formation in the isolated perfused rat liver
- PMID: 2778708
Oxygen dependence of omeprazole clearance and sulfone and sulfide metabolite formation in the isolated perfused rat liver
Abstract
Severe acute hypoxia is known to inhibit markedly the elimination of oxidatively metabolized drugs by the isolated liver. However, little is known of the degree of hypoxia required to produce inhibition of drug elimination by oxidative pathways in the intact organ. This study, in the isolated perfused rat liver, examined the oxygen dependence of the hepatic elimination of omeprazole, a drug which undergoes extensive oxidative metabolism in the rat. The relationship between hepatic oxygen supply and the production of omeprazole's oxidative sulfone and reductive sulfide metabolites was also examined. Rat livers were perfused at 15 ml/min with a perfusate containing 5 micrograms/ml of omeprazole in a single-pass design. Omeprazole clearance and the formation clearance of the two metabolites were measured in each liver during normal oxygenation, at different levels of hypoxia and after reoxygenation. There was a linear relationship between omeprazole clearance and oxygen delivery over the whole range studied. Production of the sulfone was similarly oxygen-dependent whereas the sulfide was only detectable after a significant reduction in oxygenation. In a further group of experiments the oxygen dependence of omeprazole clearance was shown to not be altered when the concentration of drug was lowered to 1 microgram/ml. This study shows that oxygen delivery is a critical determinant of the rate of oxidative drug metabolism in the isolated liver and supports the contention that reductions in hepatic oxygen supply may significantly alter the hepatic disposition of oxidatively metabolized drugs in vivo.
Similar articles
-
Corticosteroid metabolism in isolated perfused rat liver and kidney. Experimental studies with emphasis on aldosterone.Acta Physiol Scand Suppl. 1995;627:1-42. Acta Physiol Scand Suppl. 1995. PMID: 8848946 Review.
-
Oxygen dependence of salbutamol elimination by the isolated perfused rat liver.Biochem Pharmacol. 1989 May 1;38(9):1443-9. doi: 10.1016/0006-2952(89)90183-4. Biochem Pharmacol. 1989. PMID: 2719719
-
Effect of hypoxia and pregnancy on antipyrine metabolism in isolated perfused rat livers.J Pharmacol Exp Ther. 1985 Sep;234(3):584-9. J Pharmacol Exp Ther. 1985. PMID: 4032283
-
Disposition of amphotericin B in the isolated perfused rat liver.J Pharm Pharmacol. 2004 Jan;56(1):35-41. doi: 10.1211/0022357022502. J Pharm Pharmacol. 2004. PMID: 14979999
-
The effect of renal failure on hepatic drug clearance.DICP. 1991 Nov;25(11):1214-24. doi: 10.1177/106002809102501111. DICP. 1991. PMID: 1763539 Review.
Cited by
-
High level heterologous expression in E. coli using mutant forms of the lac promoter.Nucleic Acids Res. 1991 May 11;19(9):2417-21. doi: 10.1093/nar/19.9.2417. Nucleic Acids Res. 1991. PMID: 2041779 Free PMC article.
-
Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants.J Exp Med. 1995 Jun 1;181(6):1957-63. doi: 10.1084/jem.181.6.1957. J Exp Med. 1995. PMID: 7539034 Free PMC article.
-
Properties and use of botulinum toxin and other microbial neurotoxins in medicine.Microbiol Rev. 1992 Mar;56(1):80-99. doi: 10.1128/mr.56.1.80-99.1992. Microbiol Rev. 1992. PMID: 1579114 Free PMC article. Review.
-
Oral vaccination of mice against tetanus by use of a live attenuated Salmonella carrier.Infect Immun. 1990 May;58(5):1323-6. doi: 10.1128/iai.58.5.1323-1326.1990. Infect Immun. 1990. PMID: 2182542 Free PMC article.
-
Synthesis of tetanus toxin fragment C in insect cells by use of a baculovirus expression system.Infect Immun. 1991 May;59(5):1627-32. doi: 10.1128/iai.59.5.1627-1632.1991. Infect Immun. 1991. PMID: 2019434 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
