Drug biotransformation hepatic

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Brandon, E.F., Raap, C.D., Meijerman, I. etal. (2003) An update on in vitro test methods in human hepatic drug biotransformation research pros and cons. Toxicology and Applied Pharmacology, 189 (3), 233-246. 

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring ). 

The biodisposition of sedative-hypnotics can be influenced by several factors, particularly alterations in hepatic function resulting from disease or drug-induced increases or decreases in microsomal enzyme activities (see Chapter 4 Drug Biotransformation). 

Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapter 4 Drug Biotransformation and Appendix II). 

Birkett DJ, Mackenzie PI, Veronese ME, Miners JO (1993) In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci 14 292-294 Bloomer JC, Boyd HF, Hickey DMB et al. (2001) 1-(Arylpiperazinylamidoalkyl)-pyrimidones Orally Active Inhibitors of Lipoprotein-Associated Phospholipase A2. Bioorg Med Chem Lett 11 1925-1929 Brandon EFA, Raap CD, Meijerman I et al. (2003) An update on in vitro test methods in human hepatic drug biotransformation research pros and cons. Toxicol Applied Pharmacol 189 233-246... 

Variables in addition to liver blood flow that may influence the capacity of the liver to extract a drug from the blood for elimination by hepatic processes (biotransformation and/or biliary excretion of unchanged drug) are the unbound fraction in blood and the hepatic intrinsic clearance, which is a measure of the maximal ability of the liver to eliminate the drug. The hepatic clearance (with respect to blood concentrations) is determined by the following relationship between the variables which affect drug elimination by the liver ... 

Roit IM (1977) Essential immunology 3rd ed. Blackwell Scientific Oxford p. 53- Schnell RC, Means JR, Roberts SA, Pence DH (1979) Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat. Environ. Hlth. 

---