Altered Hepatic Blood Flow and Drug Disposition
For some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid.
Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice normal flow. These variations are produced by physiological, pathological or pharmacological changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearances will not be affected significantly by changes in liver blood flow.
KeywordsAntipyrine Lignocaine Phenobarbitone Hepatic Blood Flow Drug Clearance
Unable to display preview. Download preview PDF.
- Bearn, A.G.; Billing, B. and Sherlock, S.: The effect of adrenaline and noradrenaline on hepatic blood flow and splanchnic carbohydrate metabolism in man. Journal of Physiology (London) 115: 430–441 (1951).Google Scholar
- Bougas, J.; Flood, C.; Little, B.; Tait, J.F.; Tait, S.A.S. and Underwood, R.: Dynamic aspects of aldosterone metabolism in Symposium on Aldosterone, p.25–50 (Oxford, Blackwell 1964).Google Scholar
- Branch, R.A.; Jackson, L. and Roberts, C.J.C.: The relationships between liver volume and the disposition of antipyrine and indocyanine green before and after phenobarbitone treatment. British Journal of Clinical Pharmacology. In press (1975a).Google Scholar
- Branch, R.A.; James, J.A. and Read, A.E.: Major determinants of drug disposition in chronic liver disease: a study with indocyanine green and antipyrine. British Journal of Clinical Pharmacology. In press (1975b).Google Scholar
- Branch, R.A.; Shand, D.G.; Wilkinson, G.R. and Nies, A.S.: Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow. Journal of Clinical Investigation 53: 1101–1107 (1974b).PubMedCrossRefGoogle Scholar
- Hammer, W.; Idestrom, C.M. and Sjöqvist, F.: Chemical control of antidepressant drug therapy in antidepressant drugs; in Garratini, S. and Dukes, M.N.G. (Eds) Proceedings of the First International Symposium, p.301–310 (Excerpta Medica, Amsterdam 1967).Google Scholar
- Parmley, W.W. and Sonnenblick, E.H.: Glucagon: a new agent in cardiac therapy. American Journal of Cardiology 27: 293–303 (1971).Google Scholar
- Price, H.L. and Pauca, A.L.: Effects of anesthesia on the peripheral circulation. Clinical Anesthesiology 3: 73–89 (1969).Google Scholar
- Shand, D.G.; Kornhauser, D.M. and Wilkinson, G.R.: Effects of route of administration and blood flow on hepatic drug elimination. Journal of Pharmacology and Experimental Therapeutics. In press (1975).Google Scholar
- Shivery, C.A. and Vessell, E.S.: Temporal variations in acetaminophen and phenacetin half-life in man. Clinical Pharmacology and Therapeutics 18: 413–424 (1975).Google Scholar
- Vessell, E.S.; Passanati, T.; Greene, F.E. and Page, J.G.: Genetic control of drug levels and of the induction of drug-metabolizing enzymes in man: Individual variability in the extent of allopurinol and nortriptyline inhibition of drug metabolism. Annals of New York Academy of Science 179: 752–773 (1971).CrossRefGoogle Scholar