摘要:

Procainamide is almost completely absorbed after oral administration and peak plasma concentrations are generally reached within 1 to 2 hours. Upon intravenous administration there is a rapid initial distribution phase, which is completed after about 30 minutes. The pharmacokinetics can be described by a 2-compartment open model. The plasma half-life during the &bgr;-phase averdges 3 hours. The apparent volume of distribution is about 2L/kg body weight. At therapeutic plasma levels about 15% is bound to plasma proteins.Approximately 50% of administered procainamide is eliminated as unchanged drug via the kidneys. N-Acetylprocainamide is the main metabolite and is pharmacologically active, with a recovery in urine of about 15% (range 7 to 34% in healthy subjects). The acetylation of procainamide seems to be under the same monogenic control as that of isoniazid. At least 2 more metabolites have been found but are not yet identified. The renal clearance of procainamide ranges from 179 to 660ml/min. Glomerular filtration and active tubular secretion seem to be the most important mechanisms.In patients with low-output cardiac failure and/or renal impairment, the absorption, distribution and elimination of the drug may be significantly altered. Determination of plasma levels is of particular value in these cases and will contribute to more safe and effective therapy in the majority of patients. As N-acetylprocainamide seems to have pharmacological effects comparable with those of procainamide, both agents should be monitored simultaneously in order to optimise therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

After oral administration on an empty stomach, the absorption of rifampicin (rifampin) is rapid and practically complete.With a single 600mg dose, peak serum concentrations of the order of 10&mgr;g/ml generally occur 2 hours after administration. The half-life of rifampicin for this dose level is of the order of 2.5 hours.The amount of rifampicin extracted by the liver during its first passage through the hepatoportal system and transferred to bile is of relevance for the time course of distribution of the antibiotic in the blood compartment. With doses of the order of 300 to 450mg, the excretory capacity of the liver for the antibiotic is saturated. As a consequence, increasing the dose of antibiotic results in a more than proportional increase in serum concentrations.On repeated administration, and most likely as a consequence of self-induced (autoinduction) metabolism, the rate of disappearance of rifampicin from the blood compartment increases in the early phase of treatment, the phenomenon affecting mainly the levels following the peak, with a consequent reduction in half-life.Approximately 80% of rifampicin is transported in blood bound to plasma proteins, mainly albumin. Rifampicin is well distributed, although to a different degree, in the various tissues of the human body. Probably in the hepatocyte, rifampicin undergoes a process of desacetylation. The metabolic derivative, desacetylrifampicin, is more polar than the parent compound, and microbiologically active. This metabolite accounts for the majority of the antibacterial activity in the bile. Rifampicin is almost equally excreted in the bile and urine, the recovery in the 2 fluids being of the same order of magnitude.Administration of rifampicin to newborn infants and children is followed by blood levels generally lower than those found in adults for the same dose levels. In patients with impaired liver and kidney function the elimination of the antibiotic from the blood compartment is slower than in normal subjects. Rifampicin has been found to compete with bilirubin and other cholefil substances for biliary excretion, giving rise to transient and reversible increased bilirubin and BSP retention values.A kinetic model study on the transfer constants between various body compartments has indicated that rifampicin is rapidly absorbed from the intestine and that the absorption rate increases with time. Rifampicin as such is transferred into urine at a rate 3 times higher than the rate of transfer into bile. Desacetylrifampicin, the more polar metabolic derivative of rifampicin, behaves in the opposite way since its rate of transfer into bile is 4 times higher than that into urine. The rate of biotransformation of rifampicin into desacetylrifampicin is of the same order of magnitude as that of biotransformation of the latter into a further metabolic derivative, which could be a glucuronide conjugate.Administration of rifampicin to man is associated with proliferation of the smooth endoplasmic reticulum of the hepatocyte and with a state of induction of the drug metabolising enzyme system in the liver. As a result, drug metabolism interactions of clinical significance have been found between rifamipicin and drugs such as oral anticoagulants, oral contraceptives, oral sulphonylurea, hypoglycaemic agents, corticosteroids and digitoxin.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Carbamazepine seems to be as effective as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia.After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics.Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10, 11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine dose has been identified as metabolites in the urine. The quantitatively most important metabolite is the trans-10,11-dihydro-10,11-diol.The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults.A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects.Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10&mgr;g/ml (20 to 40&mgr;mol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

In a number of pathological states a decrease in the plasma protein binding of drugs is observed. This may be due to many factors related either to the protein, or the ligand (drug), or to the binding conditions. The most important of these disease states quantitatively are probably hypoalbuminaemia, conditions resulting in modification of the albumin compartment volume and the presence on albumin binding sites of pathological inhibitors of drug binding.A decrease in the extent of drug plasma protein binding does not necessarily lead to enhanced drug effects and therefore raises two important therapeutic questions. Firstly, does reduced protein binding have a clinically significant influence on the pharmacological effects of the drug? Secondly, if it does, is it preferable to modify the dosage regimen of the drug or to correct the plasma protein concentration prior to the administration of the drug? At present, only tentative answers can be given.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Drug disposition in the body is subject to marked interindividual variability. On multiple dosing, steady state plasma concentrations obtained will be inversely proportional to the body clearance of a drug metabolised according to first order kinetics. If clearance is normally distributed, the steady state will exhibit a skew distribution. The metabolic clearance of a tricyclic antidepressant was normally distributed in 35 healthy subjects, whereas an over-representation of high clearance values was found in pooled literature data for antipyrine.There is so far no evidence that the clearance of high clearance drugs shoulda priorivary more than that of low clearance drugs. If the variability in clearance is about the same, steady state plasma concentrations on multiple dosing should also have about the same dispersion. However, capacity limited elimination can be a reason for marked interindividual variability in steady state concentrations, as shown to occur, for example, with phenytoin.If drugs are very efficiently cleared by the liver, this inevitably leads to presystemic elimination of a dose administered orally. Clearance calculated after an oral dose, estimates intrinsic hepatic clearance and is a predictor for steady state plasma concentrations of such drugs. Capacity limited elimination of alprenolol, shown as a decrease in extraction of first pass elimination with increase in dose, adds to the very pronounced variability in steady state plasma concentrations encountered for this drug.Some further sources of interindividual differences in drug disposition — enterohepatic cycling, protein binding and distribution of drugs in the body — are discussed briefly.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS