摘要:

The excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk.Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk — impaired behaviour and development — is discussed from the standpoint of emerging animal data.Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the entericcoated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small (0.1 to 0.4 L/kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents.The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between 10 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the half-life can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged valproic acid accounts for only 1 to 3% of the total dose. Valproic acid is present in cerebrospinal fluid in concentrations equal to the unbound drug in plasma (around 10% of the total concentration). Valproic acid concentration in saliva is less than and unrelated to the free drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta.Four independent metabolic pathways — glucuronidation, &bgr;-oxidation and &ohgr;-oxidation (&ohgr;1and &ohgr;2) have been demonstrated in man. Analytical difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essential for the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites also show some activity.In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation. Valproic acid elimination is impaired in acute viral hepatitis and in liver cirrhosis. No information is available on valproic acid kinetics in renal insufficiency.Phenobarbitone plasma concentrations rise under combination therapy with valproic acid, because phenobarbitone elimination is impaired. Valproic acid lowers total plasma concentrations of phenytoin by displacing it from its plasma albumin binding site, but free phenytoin concentrations remain unchanged and phenytoin doses need not be modified. Valproic acid elimination is enhanced in the presence of inducing drugs like phenobarbitone, primidone, phenytoin and carbamazepine.The valproic acid dose-plasma concentration relationship is curvilinear, since valproic acid protein binding decreases with higher concentrations. Therefore, the increase in the plasma concentration is smaller than expected from the dose increase. The lower value of the therapeutic plasma concentration range of valproic acid is around 50&mgr;g/ml. Because of low clinical toxicity the upper value of the therapeutic range has yet to be determined.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The pharmacokinetics and bioavailability of cimetidine after 200mg given intravenously and orally was studied in 6 gastric and 6 duodenal ulcer patients aged between 28 and 64 years. There were no differences in any of the pharmacokinetic parameters between the two ulcer groups, but there was considerable variation which was mainly age-related.Bioavailability was not complete, but was about 60% based on the plasma concentration data. The volume of distribution at steady-state was about 80% of body weight, and the plasma clearance value of 495ml/min was mainly due to renal clearance (293ml/min). The elimination half-life was approximately 2 hours. These pharmacokinetic parameters together with the percentage of dose excreted unchanged in urine following intravenous administration were all highly age correlated; all decreasing with age except the elimination half-life which increased with age.Of clinical importance is the finding that the time for which the plasma concentration exceeded 0.5&mgr;g/ml following oral administration was also highly age-dependent, increasing by more than 2-fold in the elderly (53 to 64y) compared with the younger (28 to 45y) patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The absorption of timolol after topical administration to the eye was studied in 11 healthy volunteers and in 5 patients with bilateral open angle glaucoma. The volunteers received 2 drops of 0.5% timolol ophthalmic solution in each eye, equivalent to 0.8mg of timolol maleate. Overflow was absorbed by paper tissue. The patients received the same dose twice daily for 2 weeks and were then investigated. In the paper tissue, 12 to 88% of the dose administered was recovered. Plasma concentrations were never above 5ng/ml and not always detectable (detection limit 1 to 2ng/ml). However, timolol was absorbed as the drug was found in the urine samples from all volunteers and glaucomatous patients.

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