摘要:

The effect of advanced age on drug disposition and response is the subject of an increasing number of research studies. Cigarette smoking and other environmental factors have been shown to influence the metabolism of some drugs. Studies of the effect of age on the pharmacokinetics of antipyrine, indocyanine green and propranolol indicate that the association of increased drug metabolism and smoking occurs predominantly in the young and that apparent liver blood flow declines with age regardless of smoking habits. This age related effect of smoking on drug metabolism may reflect a reduced capacity for hepatic enzyme induction in the elderly. The relative importance of age related alterations in the intrinsic drug metabolising ability of the liver and in liver blood flow depend on the pharmacokinetic characteristics of the drug being investigated.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

A review of the literature that pertains to drug biotransformation in human fetal tissues reveals that, in spite of several publications in this comparatively new area of research, only very limited definitive information is currently available. The large majority of the studies performed have dealt with the cytochrome P-450-dependent microsomal mono-oxygenase systems and for several of the common drug metabolising reactions, very little or no data are available at this time. Some of the more important data that have emerged include observations that important bioactivation reactions can be demonstrated in human fetal tissues obtained during the period of late embryogenesis (high susceptibility to chemical dysmorphogenesis) and that the human fetal adrenal gland possesses considerable capacity to catalyse several important oxidation-reduction reactions.From the data available to date, it would appear that, in most instances, the biotransformation of drugs in the human embryo and fetus would not affect maternal plasma concentrations significantly. From the viewpoint of parameters of the pharmacokinetics of parent drug (or other xenobiotic) substrates under steady-state conditions, human fetal drug metabolism probably is of little consequence in most cases, although exceptions may exist. Pharmacokinetic parameters observed after isolated exposure, however, are very likely to be affected, perhaps markedly, in some instances.The demonstrated capacity of human prenatal tissues and cells to generate reactive intermediary metabolites, including those that produce mutations, has attracted the greatest attention recently. This capacity may be associated with extremely important adverse reactions to drugs and other environmental chemicals. Such adverse responses include transplacental mutagenesis, carcinogenesis, dysmorphogenesis, and perhaps several other undesirable effects. Although far from conclusive, the data tend to suggest that humans and subhuman primates may be more vulnerable than the smaller common experimental animals to the toxic effects of foreign organic chemicals during prenatal life. These factors should be weighed whenever exposure of pregnant women to such agents (e.g. via drug administration) is contemplated.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Drugs from a wide range of pharmacological classes are commonly given to women in childbirth, either for a maternal effect or a fetal/neonatal effect. A number of striking physiological and biochemical changes occur during labour and delivery that might alter drug kinetics.The rate of drug absorption from the gastrointestinal tract may be normal in labour provided that narcotic analgesics are not administered concurrently. Altered blood flow characteristics in the extremities could modify drug absorption from intramuscular injection sites. Drug distribution might be altered as a result of the presence of placental-fetal tissues, or as a consequence of changes in, for example, maternal blood volume, concentrations of proteins and other endogenous compounds, cardiac output or tissue perfusion. Although data are scanty on the status of the physiological determinants of drug clearance, that limited information available suggests that drug clearance could be altered in childbirth. The possibility of a placental and/or fetal contribution should not be overlooked when considering the clearance of drugs administered during labour and delivery. Uterine contractions, maternal posture and obstetric medication have been found to affect the extent of some of the physiological changes that occur. Consequently, drug disposition could be modified by these factors.All of the drugs given to women in childbirth are capable of crossing the placenta to some degree. This is a disadvantage in those cases where drugs are given for a maternal effect and may result in neonatal sequelae. The fetal exposure to, and neonatal burden at delivery of, drugs administered during labour and delivery may be influenced by many factors, including maternal posture, mode of drug administration, the drug administration to delivery interval, fetal pH, and whether intravenous bolus drug administration coincides with the contraction or relaxation phase of uterine activity.Protracted elimination by the neonate may occur for those drugs acquired in utero. Realisation of this is of considerable importance in the clinical management of the newborn.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Prazosin, a quinazoline derivative, is a peripheral vasodilator used in the treatment of arterial hypertension and more recently, congestive heart failure (CHF). Prazosin is extensively metabolised by the liver and has high first-pass metabolism and low oral bioavailability.In normal healthy volunteers, the time of peak concentration occurs between 1 and 3 hours after oral administration, with wide interindividual variations. The extent of oral absorption seems to be similar for different pharmaceutical forms and is not influenced by the presence of food in the digestive tract. Oral bioavailability of prazosin ranges from 43.5 to 69.3% (mean 56.9%). Prazosin is highly (92 to 97%) bound to human plasma proteins (albumin and &agr;1-acid glycoprotein) and the extent of binding is independent of the plasma concentration of the drug in the range of 20 to 150ng/ml. Preliminary studies in humans indicate that pathways for biotransformation of prazosin are similar to those observed in the rat and dog. Only 6% of prazosin is excreted unchanged, mainly in the urine. The two main metabolites (0-demethyl-ated) are almost completely excreted in bile. The time course of disappearance of prazosin from plasma after intravenous injection indicates that prazosin disposition should be described by a model containing at least 2 kinetically distinct compartments. The mean elimination half-life is about 2.5 hours. After intravenous administration, the steady-state volume of distribution has been calculated to be 42.2 ± 8.9L and the total body clearance 12.7 ± 1.3L/h.In hypertensive patients with normal renal function, prazosin kinetics do not differ significantly from normals. However, prazosin disposition is modified in chronic renal failure and in congestive heart failure. In both cases, the plasma free fraction of prazosin is increased and plasma elimination half-life is longer. Prazosin kinetics may be expected to be altered in patients with liver diseases. Pharmacokinetic data do not suggest a mechanism to explain the disappearance of the first-dose effect during continued administration of prazosin.Although more investigation is needed to define prazosin kinetics in congestive heart failure and chronic renal failure, the available information about prolongation of elimination half-life, decreased protein binding and increased peak plasma concentrations suggest that prazosin dosage should be titrated cautiously in such patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Strong correlations have been reported between drug concentrations at steady-state and a single drug concentration determined sometime after an initial dose for lithium, nortriptyline, imipramine, desipramine, choramphenicol and theophylline. The mathematical basis of these relationships suggests that a one point method for predicting steady-state drug concentrations and individual dosing requirements should be widely applicable to most drugs and should be valid for patients having a wide range of drug half-lives.A method is presented for evaluating the optimum time of blood sampling to determine a drug concentration in serum or plasma that best correlates with steady-state levels and for defining the range of drug half-lives beyond which the predictive approach is likely to give poor results.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The relationship between steady-state plasma concentration and clinical effect of imipramine in the treatment of nocturnal enuresis was studied in 22 hospitalised children. After 1 week on placebo the children were given imipramine in a fixed dose of about 1mg/kg for 3 weeks. The enuresis frequency decreased significantly from the placebo to the first week on imipramine, but then no further improvement was observed.There was a significant correlation between steady-state plasma concentration of desipramine or imipramine + desipramine and the reduction in enuresis frequency during imipramine treatment. The optimum effect was obtained when steady-state levels of imipramine + desipramine were above 60&mgr;g/L; i.e. the effective concentration in enuresis is 3 to 4 times lower than in antidepressive therapy.Dose- and weight-corrected, steady-state plasma concentration of imipramine and desipramine were not significantly different from those previously observed in younger adults. In 1 child, a transient rise in imipramine and desipramine concentration was seen during a period with fever and bacterial infection.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

A single oral dose of 75mg nortriptyline was given to a group of 20 depressed elderly patients in hospital. Subsequent plasma nortriptyline concentrations were used to calculate the half-life and clearance of the drug. These measurements were compared with those made previously in 17 healthy young volunteer subjects.Plasma nortriptyline half-life was longer and clearance slower (p < 0.002) in the elderly group than in the volunteers. There was no correlation of age with either of these parameters within the 2 groups, and no differences in nortriptyline pharmacokinetics could be detected between the male and female volunteer subjects. The possible reasons for these findings and their clinical consequences are discussed.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS