摘要:

The pharmacokinetics of isoniazid in man are described. Pronounced interindividual variation in circulating isoniazid concentration and clearance which occur after dosing with the drug are associated with hereditary differences in the acetylator status. The variations in rate of isoniazid inactivation and elimination in different (rapid and slow) acetylator phenotypes are primarily due to differences in the rate of acetylation of isoniazid by a genetically controlled polymorphic N-acetyltransferase in liver and small intestine. An appreciable ‘first-pass’ effect is observed following oral isoniazid administration, particularly in the rapid acetylator phenotype.Liver disease can cause a significant prolongation in the clearance of isoniazid; in the acutely ill patient, the prolongation correlates most closely with serum bilirubin elevation, although the degree of prolongation is less important than the intrinsic genetic difference between acetylator phenotypes. The effect of renal impairment on isoniazid excretion is relatively unimportant, even in slow acetylators.Methods for monitoring blood and urine concentrations of isoniazid and for acetylator phenotype determination which are convenient for the patient and clinician are available. Implications of phenotypic differences in acetylator status for the optimal management of tuberculosis with isoniazid are considered. Attempts to devise new isoniazid formulations for this purpose are being evaluated.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

Many drugs are known or suspected of having substantial first-pass hepatic metabolism in humans, and have low oral bioavailability on this basis. Hepatic disease might alter (increase) bioavailability by either or both of 2 mechanisms: decreased hepatic extraction due to impaired hepatic drug metabolising activity, or portosystemic shunting. Few studies have examined the effect of liver diseases on bioavailability, and even fewer have attempted to directly measure hepatic extraction of drugs in liver disease. Data are conflicting, with some evidence to suggest that hepatocyte function is preserved in moderate cirrhosis, while other evidence suggests a decrease in hepatic metabolic function. Several studies show relative preservation of systemic clearance in the face of substantial increases in bioavailability, suggesting that the hepatic arterial blood supply of the liver is an important determinant of systemic clearance in cirrhotic patients.Increases in bioavailability and decreases in systemic clearance have multiplicative, rather than additive, effects on area under the plasma concentration-time curve after oral administration. Clinically, there are important implications of these studies. If differences in response between patients with and without liver disease are seen after equivalent intravenous doses of a high clearance drug, the differences may be further accentuated after oral dosing. Delayed toxicity, due to accumulation of high clearance drugs is more likely to occur because of the longer half-life and larger available dose. Physicians should use extra caution in administering high clearance compounds to patients with liver disease.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

In adult man, liver blood flow amounts to roughly 100ml min-1for 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 &bgr;-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-state 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.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

There are an increasing number of clinical and experimental studies appearing in the literature suggesting that the elimination kinetics of theophylline may be dose-dependent in man. Evidence of nonlinearity includes observations that steady-state serum theophylline concentrations may increase disproportionately with increases in dose and that the elimination half-life of theophylline after multiple doses is longer than after single doses. Theophylline is apparently eliminated by parallel Michaelis-Menten and first-order kinetics.Although no specific studies of theophylline metabolism have been carried out to determine the causes of nonlinearity, it would appear that 1 -demethylation of theophylline is a potentially saturable metabolic pathway. Dietary methylxanthines or their metabolites may influence the rate of elimination of theophylline and contribute to the causes of nonlinearity.Until the elimination kinetics of theophylline have been studied in more detail as a function of dose, it would seem prudent to increase doses of theophylline cautiously to minimise the risks of adverse side effects which might be associated with unexpected accumulation of theophylline.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

摘要:

Computer simulations based on the pharmacokinetics of chloramphenicol and theophylline in patients, indicate a very strong correlation (r = 0.988 for chloramphenicol and r = 0.971 for theophylline) between log maintenance dose required to achieve a desired average drug concentration in serum at steady-state, and the drug concentration in serum 6 hours after an initial test dose administered by constant rate intravenous infusion over 0.5h. Accordingly, we have developed a nomogram to predict individual daily dosing requirements for these drugs in uncomplicated patients from asingleserum assay following an initial dose. Within defined limits, predictions made with the nomogram are essentially equivalent to those made by traditional pharmacokinetic methods which require substantially more drug concentration-time data following a test dose. Predictions based on the nomogram are relatively unaffected by small but typical errors in magnitude of the test dose, infusion time, sampling time and assay. Protocols for the administration of the test dose other than that described, e.g. administration of an oral theophylline solution, may be equally useful for dosage predictions. In principle, this approach should apply to other drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1979

数据来源: ADIS