Hepatic Drug-Metabolizing Changes

As a result of the offsetting changes in renal and hepatic clearance referred to previously, the total elimination clearance of theophylline was unchanged in the third trimester of pregnancy 

Wadelius et al. (46) found that CYP2D6 activity, known to be genetically determined, was actually increased during pregnancy in individuals who were homozygous and heterozygous extensive metab-olizers. The activity of this enzyme, however, was decreased in homozygous poor metabolizers. 

---

Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapters 4 and 66). 

Pawar SS, Mungikar AM. 1975. Changes in the activities of hepatic drug metabolizing enzymes and lipid peroxidation caused by benzene and toluene. Indian J Biochem Biophys 12 133-134. 

The hepatic clearance of drugs with an intermediate extraction ratio (Eh, 0.3-0.6) is affected by all three physiological variables blood flow to the liver, the unbound fraction in blood and the activity of hepatic drug-metabolizing enzymes. Disease-induced changes in the disposition of these drugs is least predictable. 

The effects on the liver are less pronounced. Changes in hepatic drug metabolizing enzyme activity have been demonstrated in rodents after parenteral and oral Cd treatment, although both inhibition (Hadley et al. 1974 Schnell et al. 1976, 1979) and potentiation (Johnston et al. 1975) have been reported. In the present study in females of the highest dose group a reduction in AH-activity and Cytochrome P450 concentration was observed. 

Changes in protein binding Changes in hepatic enzymes and drug metabolism (e.g., hepatic cytochrome P450 isoenzymes)... 

Woodhouse KW, Wynne HA. Age related changes in liver size and hepatic blood flow the influence of drug metabolism in the elderly. Clin Pharmacokinei 1988 15 287-294. 

Important alterations in hepatic drug excretion and metabolism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfobromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chenodeoxycholic acid is decreased. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents. 

This equation has a concentration term, C0, indicating that the half-life is variable and dependent on drug concentration. Changes in pharmacokinetic parameters that occur as a function of dose or drug concentration are referred to as nonlinear pharmacokinetic processes. Nonlinearity is usually due to saturation of protein binding, hepatic metabolism, or active renal transport of the drug.3... 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Santa Maria, C. and Machado, A., Changes in some hepatic enzyme activities related to phase II drug metabolism in male and female rats as a function of age, Mech. Ageing Dev., 44, 115, 1988. 

---