Liver pharmacodynamics

The effects of ethanol on bodily functions, e.g., those of the brain, heart, and liver, are dependent upon the systemic concentrations of ethanol over time. Therefore, the pharmacokinetics of ethanol play a pivotal role in the pharmacodynamic actions of ethanol and of its metabolic product acetaldehyde [6],... 

Numerous studies have been published on the in vivo metabolism of peptides. However, these studies are concerned mainly with assessment of pharmacokinetic parameters such as half-life and clearance. Only seldom is the in vivo biotransformation of peptides that contain only common amino acids investigated in any detail, due to the difficulty of monitoring products of proteolysis that are identical to endogenous peptides and amino acids. More importantly, such studies fail to yield mechanistic and biochemical insights. For this reason, we begin here with a discussion of the metabolism of just a few peptides in some selected tissues, namely portals of entry (mouth, gastro-intestinal tract, nose, and skin), plasma, organs of elimination (liver, kidney), and pharmacodynamic sites (brain and cerebrospinal fluid). These examples serve as introduction for the presentation in Sect. 6.4.2 of the involvement of individual peptidases in peptide metabolism. 

Another application is the esterification of menahydroquinone-4, a water-insoluble vitamin K, with V,A-dimethylglycine [144], The 1-mono, 4-mono, and 1,4-bis esters were found to be water-soluble and rapidly hydrolyzable by liver and plasma esterases. A rapid pharmacodynamic response was seen after intravenous administration of the prodrugs. 

These features are important if the sponsor intends to use the results to support a conclusion that no dosage adjustment is required for patients with impaired hepatic fxmction. Pharmacodynamic assessments may be useful in studies designed to assess the effect of altered liver fxmction, especially if concentration-response data are not available or if there is a concern that an altered hepatic function could alter the PD response. 

In a PBPK/PD model based closely on the Corley model, Reitz et al. (1990) described a pharmacodynamic end point (cytotoxicity) in the livers of chloroform-exposed animals produced by phosgene, the reactive metabolite of chloroform. 

Risk Assessment. The Reitz model is based on the assumption that cytotoxicity and reparative hyperplasia are responsible for liver neoplasia. Dose-surrogates, a more sophisticated and more accurate measure of target tissue dose derived from measuring a pharmacodynamic effect, were used. 

Elimination of clonidine is 65% by renal excretion and 35% by liver metabolism, while guanfacine and its metabolites are excreted primarily in the urine, with approximately 50% as unchanged drug. These differences in elimination may account for differences in the pharmacodynamic properties of the two drugs. The behavioral effects of clonidine last only 3 to 6... 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

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