ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Continuous ambulatory peritoneal dialysis (CAPD) is an accepted alternative to haemodialysis in the treatment of end-stage renal failure. The frequently used intraperitoneal administration of antibiotics to treat peritonitis and the possible role of CAPD in the elimination of drugs has stimulated pharmacokinetic research in this field. The 2 principal results derived from these studies are: (1) the elimination capacity of CAPD for drugs given systemically or orally is very low, and (2) drugs administered intraperitoneally rapidly enter the circulation, a significant amount of drug being absorbed from the peritoneal cavity. This pharmacokinetic behaviour is easily understood considering some basic and simple pharmacokinetic principles: the higher the volume of distribution of a substance, the lower will be the percentage of drug present in the peritoneal cavity. Thus, a prerequisite for rapid drug elimination by CAPD is a low body volume of distribution of a particular drug. Only in such a case will the drug diffuse into the peritoneal space to a significant extent. For dosing regimens in CAPD patients, the fraction of the dose eliminated by the peritoneal route should be known or estimated. This fraction depends on the relation of the peritoneal clearance to the total body clearance, and on the protein binding of the drug. The low flow rate of the peritoneal effluent (approximately 10 L/day = 7 ml/min) appears to be the most important limiting factor for the low extraction capacity of CAPD. The list of drugs that have been found to be significantly eliminated by CAPD is short: particular mention should be made of the aminoglycosides and some cephalosporins. The data on the peritoneal elimination of vancomycin are inconsistent. Although the intravenous and oral routes have been successfully used for the treatment of peritonitis, the time course of antibiotic concentrations in the peritoneal space appears to favour the peritoneal route of drug administration. During peritonitis, intraperitoneally administered drugs enter the circulation more rapidly and completely, due to the increased permeability of the peritoneal membrane. As long as the dialysate outflow rate and protein binding of the drug are not extensively altered by peritoneal inflammation, however, the extraction capacity of CAPD appears to remain low.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Therapy for inpatient burn victims is a clear challenge for the clinician, since directly following injury the pharmacokinetic parameters of many drugs will change drastically. Blood flow to the tissues is decreased; the rate of distribution and elimination of intravenous drugs administered during this time is reduced, and absorption of oral drugs may be slowed. Approximately 48 hours after injury, the blood flow increases, as does internal core temperature; the rates may increase as a result.Immediately after injury, plasma albumin level rapidly decreases and remains significantly depressed even at 60 days post-burn. Thus, the protein binding of acidic and neutral drugs will decrease and higher amounts of free fraction will be available at the biophase. On the other hand,&agr;1-acid glycoprotein increases in concentration and remains elevated at least 20 days post-burn. Basic drugs exhibit increased protein binding and will most probably need an increased dosage to achieve the appropriate pharmacological effect.Hepatic metabolism is also affected: the rate of phase I metabolism will decrease, while phase II metabolism is unimpaired and may possibly increase. Other liver functions, such as protein synthesis, are also impaired. The effect on phase I drug metabolism is believed to be due to oxygen-derived free radicals released during the course of injury.In those patients with full-thickness burns, the epidermal layer is destroyed. Topical drugs have less of a barrier to cross and, consequently, less drug is needed to achieve effectiveness. In addition, the stomach has been found to secrete excess protons which will eventually lead to ulcers in the majority of patients. Hyperchlorhydria may affect the dissolution and disintegration of orally administered drugs in tablet form, as well as the partitioning of the neutral un-ionised species between the stomach and bloodstream. In the small intestine decreased nutrient absorption and DNA synthesis occurs, but the effect this may have on drug absorption is questionable.This paper focuses on the epidemiology of burn injuries and the way in which the pathophysiology following such injury alters the pharmacokinetics of a drug. Specific examples are provided. Some mention is made of burn management, therapeutic drug monitoring in burn patients, experimental design considerations, and future research topics.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Part I of this article, which appeared in the previous issue of the Journal, covered the drug interactions affecting the pharmacokinetics of phenytoin. The influence of phenytoin on the gastrointestinal absorption and plasma protein binding of other drugs was also discussed.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Decisions about the safety of breast feeding during maternal ingestion of drugs require knowledge of the amount of drug which might be present in the milk. For many drugs this has not been studied, and mothers are usually advised against breast feeding. In many cases this is undoubtedly unnecessary, as the total dose to which the baby is exposed is often negligible. It would be very helpful, therefore, to be able to predict the approximate amount of drug which might be present in milk.Existing theory of pH partitioning enables estimation of the distribution of unbound drug, i.e. milk: plasma unbound ratios. However, these ratios are poor estimates of the concentration ratios for whole milk, because whole milk contains proteins and lipid in which drugs will distribute in amounts which depend on their particular physicochemical properties.To predict the milk: plasma concentration ratios for whole milk, the amount of drug present in the protein and lipid phases must be considered along with the unbound drug distribution. A ‘phase distribution model’ has therefore been developed which permits estimation of whole milk: plasma concentration ratios.The model requires a knowledge of the unbound drug concentration ratio, the plasma and milk unbound fractions and the milk lipid: ultrafiltrate partition coefficient. Evaluation of the model by comparison of predicted whole milk ratio values with literature milk: plasma area under the curve (AUC) ratios indicated a trend to overprediction for acidic and neutral drugs and underprediction for basic drugs. Transformation of the phase distribution equation by taking logarithms results in a relationship which can be analysed by multiple linear regression to derive predictive equations for acidic and basic drugs which take into account the relative contributions of each component of the model. Regression of the logarithms of the literature milk: plasma AUC values against the independent variables resulted in good correlations for acidic and basic drugs. The independent variables explained 93.1% and 82.9% of the variance in the values for acidic and basic drugs, respectively, with random scatter of residuals.The equations, together with those to predict unbound fractions of drug in milk and milk lipid: ultrafiltrate partition coefficients, enable the ratio of the milk: plasma AUCs to be estimated for any acidic or basic drug for which the distribution into human milk is not known, using the pKa, octanol: water partition coefficient and plasma protein binding values of the drug. The data set for neutral drugs (n = 3) was too small to develop a correlation equation.The predicted milk: plasma ratio of the 2 AUCs enables the infant dose rate to be calculated using the measured or estimated maternal steady-state plasma concentration and the volume of milk ingested.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The steady-state renal clearance of cefsulodin was studied in 6 patients with cystic fibrosis and 8 healthy controls. The drug was administered by constant rate infusion to obtain 2 values of plasma concentration, 2 and 30 mg/L. As an estimate of the glomerular filtration rate, the renal clearance of inulin was measured simultaneously.The results showed the figures for inulin clearance to be approximately 30% higher in cystic fibrosis patients than in healthy controls at both concentrations, and a corresponding increase in the renal clearance of cefsulodin was seen in patients over controls. The ratio between the renal clearances of the 2 substances was on average 0.9 in both groups.The correlation found between the 2 renal clearances (r = 0.75; p < 0.001) indicates that glomerular filtration rate has considerable influence on the renal elimination of cefsulodin. This finding emphasises the importance of glomerular filtration rate for the renal clearance of drugs in cystic fibrosis.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS