摘要:

First-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration (corrected for dosage if necessary), is often used as a measure of the extent of first-pass metabolism. When several sites of first-pass metabolism are in series, the bioavailability is the product of the fractions of drug entering the tissue that escape loss at each site.The extent of first-pass metabolism in the liver and intestinal wall depends on a number of physiological factors. The major factors are enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility. Models that describe the dependence of bioavailability on changes in these physiological variables have been developed for drugs subject to first-pass metabolism only in the liver. Two that have been applied widely are the ‘well-stirred’ and ‘parallel tube’ models. Discrimination between the 2 models may be performed under linear conditions in which all pharmacokinetic parameters are independent of concentration and time. The predictions of the models are similar when bioavailability is large but differ dramatically when bioavailability is small. The ‘parallel tube’ model always predicts a much greater change in bioavailability than the ‘well-stirred’ model for a given change in drug-metabolising enzyme activity, blood flow, or fraction of drug unbound.Many clinically important drugs undergo considerable first-pass metabolism after an oral dose. Drugs in this category include alprenolol, amitriptyline, dihydroergotamine, 5-fluorouracil, hydralazine, isoprenaline (isoproterenol), lignocaine (lidocaine), lorcainide, pethidine (meperidine), mercaptopurine, metoprolol, morphine, neostigmine, nifedipine, pentazocine and propranolol. One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations. For some drugs, extensive first-pass metabolism precludes their use as oral agents (e.g. lignocaine, naloxone and glyceryl trinitrate). Inhalation or buccal, rectal or transdermal administration may, in part, obviate the problems of extensive first-pass metabolism of an oral dose.Drugs that undergo extensive first-pass metabolism may produce different plasma metabolite concentration-time profiles after oral and parenteral administration. After an oral dose, the concentration of the metabolite may reach a peak earlier than after a parenteral dose. Sometimes, metabolites have only been detected in plasma after an oral dose. Drugs in this category include alprenolol, amitriptyline, lorcainide, pethidine, nifedipine and propranolol. Although the plasma concentration-time profiles of metabolites may differ after oral and parenteral doses, the fraction of a dose eventually converted to a metabolite should be the same after each route of administration provided that the ingested drug is completely absorbed, is eliminated solely by metabolism in the liver, and has linear kinetics. Otherwise, the fraction of a dose administered that is converted to a metabolite may vary with route of administration (e.g. with isoprenaline and salbutamol). Variation in the concentration ratios between parent drug and metabolite may produce route-dependent differences in pharmacological and toxicological responses to a given concentration of the parent drug (e.g. with encainide, lorcainide, quinidine and verapamil).Drugs that undergo extensive first-pass elimination exhibit pronounced interindividual variation in plasma concentrations or drug concentration-time curves after oral administration. This variation, often reflected in variability in drug response, poses one of the major problems in the clinical use of these drugs. Variability in first-pass metabolism is accounted for by differences in metabolising enzyme activity produced either by enzyme induction, inhibition, or by genetic polymorphism. Liver disease affects bioavailability by changing metabolising enzyme activity and plasma protein binding, and creating intraand extrahepatic portacaval shunts. In addition, food, by causing transient increases in splanchnic-hepatic blood flow, may also decrease the first-pass metabolism of certain drugs.The bioavailability of some drugs is dose- and time-dependent. The bioavailability of a single oral dose of 5-fluorouracil, hydralazine, lorcainide, phenacetin (acetophenetidin), propranolol and salicylamide increases as dose increases. When lorcainide, metoprolol, propranolol, dextropropoxyphene (propoxyphene) and verapamil are given repeatedly, their bioavailability increases. This time dependency may not be observed when the drugs are administered intravenously.The liver has been most extensively studied with respect to first-pass metabolism. Relatively little information is available in humans on intestinal or pulmonary metabolism or on the effects of altered organ blood flow and plasma protein binding on first-pass metabolism. These potentially important areas require further exploration to broaden our understanding of the clinically important phenomenon of first-pass metabolism.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Verapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels.Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism. with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound inin vitrostudies.After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug.Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, ‘standard’ dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil's disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and &bgr;-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Haemodialysis is utilised therapeutically as supportive treatment for end-stage renal disease (ESRD). In conjunction with haemodialysis therapy, ESRD patients frequently receive a large number of drugs to treat a multitude of intercurrent conditions. Because of the impaired renal function in ESRD patients, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs and active metabolites with extensive renal excretion. On the other hand, if the removal of a drug by haemodialysis during concomitant drug therapy is significant, a dosage supplement would be required to ensure adequate therapeutic efficacy. Knowledge of the impact of haemodialysis on the elimination of specific drugs is therefore essential to the rational design of the dosage regimen in patients undergoing haemodialysis.This review addresses the clinical pharmacokinetic aspects of drug therapy in haemodialysis patients and considers: (a) the effects of ESRD on the general pharmacokinetics of drugs; (b) dialysis clearance and its impact on drug and metabolite elimination; (c) the definition of dialysability and the criteria for evaluation of drug dialysability; (d) pharmacokinetic parameters which are useful in the prediction of drug dialysability; and (e) the application of pharmacokinetic principles to the adjustment of dosage regimens in haemodialysis patients. Finally, drugs commonly associated with haemodialysis therapy are tabulated with updated pharmacokinetics and dialysability information.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

In this article, many of the reports which describe the various assay procedures for 8 of the most commonly monitored drugs in plasma (digoxin, gentamicin, phenobarbitone, phenytoin, procainamide, quinidine, salicylates and theophylline) are reviewed, together with studies dealing with interferences of other drugs with these assays. Factors which are evaluated include whether the interference was studied when the drug was taken by a patient or a volunteer or by adding it to serumin vitro,the concentration or dose of the interfering drug (when reported), and the clinical implications of the interference. Suggestions as to how to eliminate some of these potential sources of interference are made.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The single-dose pharmacokinetics of intravenously and orally administered tinidazole were studied in normal subjects and patients with severe chronic renal failure. The clearance of tinidazole was also measured in patients on regular haemodialysis.After intravenous administration the mean elimination half-life of tinidazole was 17.1 ± 2.3 (SD) hours in the normal subjects and 16.9 ± 4.9 hours in patients with renal failure; the mean apparent volumes of distribution were 0.80 ± 0.09 L/kg and 0.69 ± 0.09 L/kg, respectively. Following oral administration the mean elimination half-life was 15.6 ± 1.6 hours in the normal subjects and 18.4 ± 3.5 hours in patients with renal failure; there were no statistically significant differences in these pharmacokinetic parameters. There was no accumulation of the major metabolite (hydroxymethyl tinidazole) in normal subjects or in patients with renal failure. Tinidazole clearance during haemodialysis was 71 ± 7.7 ml/min.In the presence of renal failure no modification of tinidazole dosage would appear to be necessary. Tinidazole should be administered in full dosage following haemodialysis.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS