ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined.Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order).Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug.Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called ‘cheese effect’ is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxicationper se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Valaciclovir and famciclovir, two new prodrugs (for aciclovir and penciclovir, respectively) have similar pharmacokinetics in many regards. Both have good but incomplete bioavailability, with the conversion to the active forms taking place in the liver, but by different cytosolic enzymes. Absorption and conversion are consistent in relevant patient groups, including those with liver disease. The pharmacokinetics of both active molecules are also similar in being mainly renally eliminated, a significant component of which is tubular secretion, and elimination half-lives from plasma of approximately 2.2 to 2.5 hours. Dosage adjustment is required in the presence of renal impairment. No clinically important drug interactions have been identified with either drug. The choice between the two agents is likely to depend on clinical factors such as tolerability, safety, efficacy, compliance and possibly cost, rather than on their pharmacokinetics.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

This article is the second part of a review of the pharmacokinetics of antiepileptic drugs (AEDs) in paediatric patients. It reviews 139 papers published since 1969 on the pharmacokinetics of phenytoin, carbamazepine, sulthiame, lamotrigine (phenyltriazine), vigabatrin, oxcarbazepine and felbamate in this population.The pharmacokinetics of phenytoin are significantly affected by age. The terminal elimination half-life (t½z) is relatively long in neonates; it then decreases during the first postnatal month to lower values than in adults, and then progres-sively increases with age due to an age-dependent decrease in the metabolic rate. Rate of elimination is strongly dose-dependent at all ages. The combination of these factors makes it difficult to predict what plasma concentrations would result from dose per kilogram (dose/kg) adjustments in neonates and children, especially when phenytoin is coadministered with other liver enzyme-inducing drugs, such as phenobarbital and carbamazepine. The concentration of phenytoin in brain and other tissues depends on the unbound/total concentration ratio. For neonates this ratio is higher than that found in adults; it then decreases over the first 3 postnatal months to approach adult values. The fraction of unbound phenytoin is significantly higher in patients also receiving valproic acid.Carbamazepine is almost completely epoxidised to the active metabolite carbamazepine epoxide, which is in turn converted to carbamazepine diol. Metabolic conversion of carbamazepine and renal clearance of carbamazepine diol are much higher in children than in adults; t½zof carbamazepine is thus very short in young children, increasing with age. No data are available on the neonatal period. The carbamazepine epoxide/carbamazepine ratio may be significantly increased by metabolic inducers (e.g. phenytoin, phenobarbital and primidone) or by inhibitors of the carbamazepine epoxide to carbamazepine diol conversion (e.g. valproic acid). Macrolides inhibit carbamazepine metabolism, thus increasing carbamazepine plasma concentrations. Drug-induced changes in carbamazepine kinetics are particularly pronounced in children.In children, a higher dose/kg of sulthiame, lamotrigine, oxcarbazepine and felbamate than in adults is required to obtain an effective plasma concentration. The published data do not support the use of a different dose/kg of vigabatrin in children aged between 1 month and 15 years.The pharmacokinetic information in the paediatric literature may help in assessing AED prescriptions in childhood to prevent seizures and AED-related adverse effects on the ongoing maturational processes of the brain.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area.Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories.In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis.A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine.Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination.Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, ‘safe’ drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics.In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless of the route of elimination of drug or metabolite.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS