Drug Kinetics and Hepatic Blood Flow

Summary

In adult man, liver blood flow amounts to roughly 100ml min⁻¹ for every 100g of liver (range 1.1 to 1.8 litres min⁻¹) of which 70 to 75% is supplied via the portal vein.

For certain drugs, when given intravenously, the liver represents the sole site of metabolic transformation and less than 10 % is eliminated unchanged by other routes. For these chemicals, the amount removed from the body in unit time depends on their rate of presentation to the healthy liver: thus, clearance depends on and approximates to hepatic blood flow. Such agents undergo extensive extraction at each circulation through the liver, the magnitude of this being determined largely by the activity of drug metabolising enzymes located therein. When such drugs are administered orally, there is extensive presystemic elimination which limits their bioavailability even though they are almost completely absorbed. Drugs which exhibit this type of pharmacokinetic pattern, include the antiarrhythmic agents lignocaine (lidocaine), lorcainide and Verapamil; also lipid-soluble β-adrenoceptor antagonists including alprenolol, labetalol, metoprolol, Oxprenolol and Propranolol. The opiate analgesics, morphine, pentazocine, pethidine (meperidine) and propoxyphene, as well as the antagonist, naloxone, show a similar pharmacokinetic pattern. Other examples include the CNS active compounds, imipramine, nortriptyline, chlormethiazole and methohexitone. Because the liver is their almost exclusive site of metabolic clearance it is possible to use one or more of these drugs to estimate hepatic blood flow in intact man.

Hepatic blood flow and hence systemic clearance of such drugs is influenced by posture, exercise and perhaps by food. Hepatic blood flow decreases in old age and results in a prolongation in the half-lives of intravenously administered Propranolol, lignocaine and chlormethiazole. In addition, there is evidence of diminished microsomal enzyme activity in the elderly, especially in the presence of inducers of microsomal enzyme activity, leading to an increased bioavailability of these drugs after oral administration.

Thyrotoxicosis is associated with an increased clearance of such drugs and a reduction in their steady-stale plasma concentrations, whereas oppposite effects are seen in myxoedema. Similarly, heart failure leads to a reduction in their rates of elimination, either because of a diminished cardiac output or through an alteration in the distribution volume. Effects of hepatic disease are complex and vary according to the type and chronicity of liver pathology, the presence of hepatic failure and concurrent drug therapy. In general, acute viral hepatitis produces little change in drug pharmacokinetics whereas chronic liver disease (particularly cirrhosis) leads to a prolongation of their half-lives and diminished systemic clearances. The changes are most prominent after oral administration of such drugs and are manifest as an increased bioavailability.

Concurrent drug therapy can affect the pharmacokinetics of drugs like Propranolol either by altering hepatic blood flow — catecholamines and glucagon for example — or by changing the extraction ratio through an effect on enzyme activity in the liver.