Pharmacology hepatic clearance

The analysis was completed for 12 compounds for which protein binding, renal and hepatic clearances and microsomal data were available. Plasma concentration versus time profiles in the rat were also available for these compounds. The approach taken was to simulate the individual processes (metabolic clearance, renal clearance, distribution, pharmacological activity). The ability of the PBPK model to simulate the in vivo behavior of the compound was verified in the rat. Thus, the metabolic clearance of the compounds could be reasonably well simulated, based on microsomal data and assuming no binding to microsomes less than twofold deviation between the observed and predicted clearance was achieved for about eight of the... 

The uptake, redistribution and protein binding of methohexitone are somewhat similar to that of thiopentone. Although methohexitone is less lipid soluble than thiopentone, a greater proportion (75%) is non-ionised at body pH and therefore available for pharmacological effect. Hepatic clearance (11 mL-kg-l-min-1) is higher for methohexitone than for thiopentone and the elimination half-life considerably shorter ( 4 hours). While cumulation is less likely to occur with repeated doses, prolongation of anaesthetic effect has been demonstrated when methohexitone was infused for longer than 60 minutes. 

When used concomitantly, theophylline increases the excretion of lithium. Also, cimetidine, allopurinol (high dose), propranolol, erythromycin, and troleandomycin may cause an increase in serum concentrations of theophylline by decreasing the hepatic clearance. Barbiturates and phenytoin enhance hepatic clearance and hepatic metabolism of theophylline, decreasing plasma levels. Beta-adrenergic blockers exert an antagonistic pharmacologic effect. 

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so usual doses may lead to toxic concentrations of the drug in patients with liver disease. Conversely, clearance may be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear theophylline faster than adults (1-1.5 mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 60 Special Aspects of Perinatal Pediatric Pharmacology). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely. 

Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including TV-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. 

Dr. Meskin s major areas of research interest include (1) hepatic drug metabolism and the effects of nutritional factors on drug metabolism and clearance (2) nutrient-drug interactions (3) the role of bioactive non-nutrients (phytochemicals, herbs, botanicals, and nutritional supplements) in disease prevention and health promotion (4) fetal pharmacology and fetal, maternal, and pediatric nutrition (5) nutrition education and (6) the development of educational programs for improving science literacy and combating health fraud. 

Drug clearance is slow due to pharmacologic properties of intoxicant or patient s impaired renal or hepatic function... 

As emphasized in Chapter 23, neonates are especially vulnerable to ADRs because they are sometimes exposed to drugs before birth and have immature renal and hepatic drug clearance capacities. Additionally, there is insufficient information on the clinical pharmacology of various drugs in this age group to guide rational pharmacotherapy (38, 39). 

Wilkinson, G.R. Shand, D.G. (1975) A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics, 18, 377-390. 

Valproic add modulates the action of various other common antiepileptic drugs. It inhibits the nonrenal clearance of phenobarbital, resulting in elevated phenobarbital levels. It competes -with phenytoin for protein-binding sites. The free phenytoin concentration remains approximately the same, but the total phenytoin in the plasma decreases. Because the free phenytoin concentration remains unchanged, the pharmacological effect is retained. Other common antiepileptic drugs that induce hepatic oxidative enzymes result in increased valproic acid clearance this increased clearance rate requires a higher dose to maintain effective therapeutic levels. 

The total plasma concentration of lidocaine is a result of clearance of the drug and is modulated by hepatic function. There is little impact on clearance in renal disease. In situations of decreased organ perfusion, clearance is reduced and increased blood concentrations of lidocaine should be expected reduced dosing is appropriate in these circumstances. The principal binding protein of Hdocaine, AAG, has been demonstrated to accumulate after myocardial infarction. The result of accumulation of this protein is reduction of free lidocaine, which reduces the pharmacological effect of the drug. Lidocaine is usually analyzed by immunoassay, and MEGX and GX by HPLC. 

These substances metabolized within the CNS illustrate well one of the difficulties that may be encountered with prodrug kinetics. The prodrug may follow an ADME pattern perfectly well described by its systemic availability, volume of distribution, and both hepatic and renal clearances, but still have a pharmacological effect whose dependency on blood kinetics is only indirect. This is particularly true if the drug must diffuse through the blood-brain barrier, and is then metabolized by enzyme systems different from those found in the liver. 

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