摘要:

The effects of impaired renal function on drug disposition and responsiveness have generally been examined with respect to alterations in the behaviour of unchanged drug. For drugs which are extensively excreted via the kidneys various approaches have been applied to modify dosage regimens in order to optimise drug concentration-time profiles. However, it is now recognised that even if urinary excretion is not an important route of drug elimination, renal failure may affect the body's handling of a drug and its clinical effects. This may occur by the greater than normal accumulation of drug metabolites which are predominantly excreted in the urine, leading to a situation analogous to coadministration of another drug and the possible sequelae of a drug-drug interaction.The accumulation of pharmacologically and/or toxicologically active metabolites in renal failure occurs in several instances and can significantly alter clinical effects at the pharmacodynamic level. Accumulated inactive metabolites, especially those formed by conjugation with glucuronic acid, may also lead to a change in drug action by way of regeneration of the parent drug. This in turn may alter the disposition characteristics of the precursor drug even though urinary excretion is not an important pathway of elimination in individuals with normal renal function.It is also possible that metabolites may have a direct dispositional interaction with the parent drug. This would most likely occur through competition for non-linear processes such as plasma and tissue binding, active transport and enzyme-mediated reactions. The degree of such inhibition would be dependent on the relative affinities and concentrations of the interacting compounds, and thus renal failure could exaggerate this type of phenomenon. However, these types of interactions are not well substantiated, probably because of their complexity and subtlety.The higher than normal accumulation of metabolites in renal failure may also affect diagnostic procedures either directly or indirectly. For example, the metabolite may interfere with the analysis of an endogenous compound used for diagnostic purposes. Alternatively, the disposition of the drug may be used in a diagnostic fashion, as occurs with the determination of drug acetylation phenotype. In the latter instance, methodologies based on parent drug-metabolite ratios in the plasma and/or urine may well be misleading when applied to patients with impaired renal function.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

Nitrazepam is one of the oldest benzodiazepines and is widely used as an hypnotic throughout the world, except North America, where it is not available. It is a safe hypnotic, with low acute toxicity and minor side effects. Development of tolerance or dependence and withdrawal symptoms are rare and very few known interactions with other drugs exist.The absorption of nitrazepam from the gastrointestinal tract is fairly rapid (tmaxranging 0.5 to 7 hours). The bioavailability after oral intake averages about 80%. Maximum plasma concentrations after a single 5mg dose are of the order of 40ng/ml. As a lipophilic drug, nitrazepam is distributed rapidly in the body. The plasma levels can be fitted to a 2-compartment open model. The &agr;-phase is rather rapid and the elimination phase is characterised by a long half-life of about 30 hours; accumulation with daily use therefore occurs. Marked interindividual variation (up to 10-fold) is found in all pharmacokinetic parameters. Age and immobilising diseases may influence the parameters, evidently increasing Vd&bgr;and t1/2&bgr;.A similar amount of protein-free drug found in the plasma, i.e. 10 to 15% of the total plasma level, is found in the cerebrospinal fluid. In saliva the concentrations are significantly smaller. Nitrazepam penetrates the human placenta. In early pregnancy, the ratio of cord to maternal plasma concentration is about 0.5, 12 hours after drug administration. In late pregnancy, the ratio reaches 1 within a few hours. Breast milk concentrations are about one-half of those in maternal plasma.Nitrazepam has no clinically active metabolites. It is excreted mainly as conjugated and non-conjugated 7-aminonitrazepam and 7-acetamidonitrazepam. Polymorphic acetylation is not likely to be of clinical importance. Enzyme induction or significant loss of efficacy have not been found with long term use.There is no significant correlation between plasma concentrations and clinical effects (or side effects) of nitrazepam. Plasma level monitoring is therefore of no benefit clinically (except for special cases, e.g. in epileptic patients). Increased responsiveness in terms of therapeutic effects and side effects is evident in the elderly. Therefore, small doses not exceeding 5mg daily should be prescribed for geriatric patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

The binding of the basic drugs quinidine, propranolol and amitriptyline, the neutral drug digitoxin and the acidic drug phenytoin to heparinised normal plasma, to orosomucoid (&agr;1-acid glycoprotein)-deficient plasma and to purified orosomucoid and albumin was studied in both the presence and absence of tris (2-butoxyethyl)-phosphate (TBEP) and di-(2-ethylhexyl)-phthalate (DEHP).The addition of TBEP and DEHP to heparinised plasma in concentrations up to 2.5mmol/L markedly increased the unbound fractions of quinidine and propranolol, but the increase was less for amitriptyline, TBEP being the most potent displacer. In orosomucoid-deficient plasma, which was prepared by immunoprecipitation, the free fraction of quinidine was similar to that of normal plasma in which maximal displacement with TBEP was obtained. The addition of the displacers to orosomucoid-deficient plasma caused no further reduction in the binding, nor was the plasma binding of digitoxin and phenytoin significantly affected. When combining purified albumin and orosomucoid in concentrations found in normal plasma, quinidine binding approached that of heparinised normal plasma.This study confirms the dominant role of orosomucoid in the variable plasma binding of basic drugs, and underlines the value of using immunologically prepared orosomucoid-deficient plasma and TBEP or DEHP as model displacers.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

The selective &bgr;1-adrenoceptor antagonist metoprolol is eliminated primarily by hepatic metabolism and usually less than 5% of an oral dose is excreted unchanged in the urine.The effects of impaired liver function on the pharmacokinetics of metoprolol were studied in 10 patients with hepatic cirrhosis. All subjects were given single doses of 20mg intravenously and 50mg orally on separate days. The mean fraction of the drug available systematically was 84 ± 10% in patients and 50 ± 11% in a control group of 6 healthy subjects (p < 0.05). The total body clearance of metoprolol in the cirrhotics was 0.61 ± 0.13L/min and in the controls 0.80 ± 0.11L/min. These values correspond to elimination half-lives of 7.2 ± 1.2 and 4.2 ± 1.1 hours, respectively. The differences were not statistically significant. Impaired liver function had no effect on the volume of distribution of metoprolol. Total body clearance was weakly but linearly related to galactose clearance (r2= 0.52; p < 0.05), and the half-life was related to serum bilirubin (r2= 0.74; p < 0.01).

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

The half-life and metabolic clearance rate (MCR) of antipyrine and phenytoin were determined in 14 young [mean age: 28.8 ± 8.3 (SD) years] and in 14 elderly [mean age: 83.5 ± 7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent difference in drug metabolism could be explained by a reduced liver weight with age.The size of the liver was smaller in the elderly subjects even when related to decreased body surface. A significant decrease in serum albumin in the elderly compared with the younger group was also noted. The half-life of antipyrine was significantly longer in the elderly than in the younger group, 756 ± 318 and 465 ± 110 minutes, respectively, and the MCR was correspondingly lower in the elderly even when calculated per litre of liver volume, 22.8 ± 7.8 and 36.3 ± 8.9ml/minute/L liver volume, respectively. No significant differences in the 2 age groups were found in half-life and total clearance of phenytoin, but a reduced free phenytoin clearance was demonstrated in the elderly (240 ± 92ml/minute/L liver volume) compared with the younger (325 ± 81 ml/minute/L liver volume) group. No significant correlation was found between liver volume and the half-life of antipyrine and phenytoin. However, a significant correlation was demonstrated between liver volume and MCR of antipyrine as well as between total and free clearance of phenytoin. No correlation was found between the half-lives of the 2 drugs, while a significant correlation existed between the clearance values.It is suggested that the age-dependent reduction in drug clearance is due not only to a smaller liver volume, but is also a result of a reduced capacity of the liver microsomes per unit of liver in the elderly. With regard to age-dependent changes in drug metabolism, the protein binding of the actual drug has to be taken into consideration.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS