ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

The skin is an evolutionary masterpiece of living tissue which is the final control unit for determining the local and systemic availability of any drug which must pass into and through it.In vivoin humans, many factors will affect the absorption of drugs. These include individual biological variation and may be influenced by race. The skin site of the body will also influence percutaneous absorption. Generally, those body parts exposed to the open environment (and to cosmetics, drugs and hazardous toxic substances) are most affected. Treating patients may involve single daily drug treatment or multiple daily administration. Finally, the body will be washed (normal daily process or when there is concern about skin decontamination) and this will influence percutaneous absorption.The vehicle of a drug will affect release of drug to skin. On skin, the interrelationships of this form of administration involve drug concentration, surface area exposed, frequency and time of exposure. These interrelationships determine percutaneous absorption. Accounting for all the drug administered is desirable in controlled studies. The bioavailability of the drug then is assessed in relationship to its efficacy and toxicity in drug development.There are methods, both quantitative and qualitative,in vitroandin vivo,for studying percutaneous absorption of drugs. Animal models are substituted for humans to determine percutaneous absorption. Each of these methods thus becomes a factor in determining percutaneous absorption because they predict absorption in humans. The relevance of these predictions to humansin vivois of intense research interest.The most relevant determination of percutaneous absorption of a drug in humans is when the drug in its approved formulation is appliedin vivoto humans in the intended clinical situation. Deviation from this scenario involves the introduction of variables which may alter percutaneous absorption.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Vigabatrin is a structural analogue of the inhibitory neurotransmitter&ggr;-aminobutyric acid (GABA). It is supplied as a racemic mixture, with theS(+) enantiomer possessing pharmacological activity. [R,S]-Vigabatrin plasma concentrations can be estimated using high-performance liquid chromatographic methods. Only gas chromatography-mass spectrometry methods allow quantification of theS(+) andR(−) enantiomers.Vigabatrin was rapidly absorbed reaching peak concentrations within 1 to 2h. Area under plasma concentration-time curves indicated dose-linear pharmacokinetics. There was no effect of food on the absorption of vigabatrin. The absorption characteristics of the enantiomers were similar to those of the [R,S]-vigabatrin. No chiral inversion was detected after administration of the pureS(+) enantiomer. Vigabatrin is not protein bound. The apparent volume of distribution of [R,S]-vigabatrin was approximately 0.8 L/kg. Despite the lack of protein binding, cerebrospinal concentrations of the [R,S]-vigabatrin were only 10% of the plasma concentration 6h after a single oral dose. The half-life of [R,S]-vigabatrin was between 5.3 and 7.4h, the half-life of the enantiomers were 7.5 and 8.1h for theS(+) and theR(−) forms, respectively. The major route of elimination was renal excretion; urinary recovery of the [R,S]-vigabatrin was close to 70%.Pharmacokinetic studies in epileptic children did not show any significant effect of maturation on the disposition of theS(+) enantiomer: the half-life and the renal clearance were similar to adult values. Data suggest a lower bioavailability in children. In adults with epilepsy, the half-life of the [R,S]-vigabatrin ranged from 4.2 and 5.6h, similar to that measured in healthy adults. In elderly nonepileptic volunteers the pharmacokinetics of the enantiomers of vigabatrin showed delayed absorption, a major increase in peak concentration and a prolonged half-life. These changes were attributed to decreased renal clearance of vigabatrin. A nonlinear relationship between renal clearance and creatinine clearance was suggested.Vigabatrin caused a 20% fall in plasma phenytoin concentrations, the mechanism of which has not been elucidated. There were no other interactions with most concurrently administered anticonvulsants.The usual dosage of vigabatrin as add-on treatment in adults is 2 to 4g daily. Higher dosages up to 80 mg/kg daily were required in children. A dosage adjustment was recommended in any patient with decreased renal clearance.Although anticonvulsant effects were clearly related to dosage, monitoring of plasma concentrations of vigabatrin as a guide to dosage is unlikely to be of as much value as with other antiepileptic drugs. The action of the drug long outlasts its presence in plasma.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Amphotericin B remains a very important drug for the treatment of fungal infections despite its toxicity. Encapsulation of amphotericin B into liposomes appears to reduce the toxic effects and to improve the clinical efficacy, allowing higher dosages to be given. The exact mechanism behind the reduced toxicity is not yet known.Amphotericin B is widely distributed after intravenous administration as the deoxycholate solubilisate. The highest concentrations are found in the liver, spleen and kidney. Protein binding and binding to the tissues is very high. The fate of the drug in the body is not known in detail. Renal and biliary excretion are both low and no metabolites have been identified. The drug is still detectable in the liver, spleen and kidney for as long as 1 year after stopping therapy.The pharmacokinetics of the different liposomal amphotericin B or lipid complexes of amphotericin B. which were recently developed, are quite diverse. A number of these preparations, such as amphotericin B lipid complex (ABLC). ‘AmBisome’ and amphotericin B colloidal dispersion (ABCD) are in clinical development. Their pharmacokinetics depend to a large extent on the composition and particle size of the liposomes or lipid complexes. Relatively large structures such as ABLC are rapidly taken up by the mononuclear phagocyte system, whereas smaller liposomes remain in the circulation for prolonged periods. In all studies only the total amphotericin B (both free and liposome- or lipid-associated) concentrations were determined.There is a need for studies correlating clinical efficacy and tolerability of liposomal amphotericin B with the pharmacokinetic properties of these formulations.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Glucuronides of drugs are considered to be generally inactive and rapidly eliminated. Therefore, these metabolites are often not taken into account in evaluating drug effects. The present review describes examples of both direct and indirect contributions of glucuronides to net drug effects. Multiple lines of evidence indicate that morphine-6-glucuronide has analgesic activity. This compound has a high affinity to the μ-receptor, is capable of penetrating the blood/brain barrier and is a potent analgesic after administration to patients. Indirect activity of glucuronides may consist of a systemic cycle in which an active parent compound is derived from the glucuronide by enzymatic action. Such systemic cycling has been demonstrated for clofibric acid. In addition, some acyl glucuronides are subject to intramolecular rearrangement and the resulting metabolites are resistant to &bgr;-glucuronidase. Covalent protein binding of glucuronides by different mechanisms may contribute to drug toxicity and immune responses. If glucuronides are accepted as potential modifiers of net drug action it is important to determine what factors modulate disposition of these compounds. Therefore, the later section of this review describes glucuronidation under different pathophysiological conditions. Examples for alterations of the rate and/or extent of glucuronidation by concurrent disease processes, age and coadministration of other drugs are provided.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

The pharmacokinetic disposition of sulfasalazine and its metabolites was studied in 8 young and 12 elderly patients with active rheumatoid arthritis. Equal numbers of slow and fast acetylators were included in each age group. Patients received enteric-coated sulfasalazine 2g daily for 21 days; specimens of serum and urine were collected for 96h after administration on days 1 and 21. The elimination half-life of sulfasalazine was greater in the elderly patients. Many disposition parameters of sulfapyridine differed in slow and fast acetylators; of greatest significance were the increased values of steady-state serum concentration in the slow acetylators. There was no effect of age on any sulfapyridine disposition parameters. Values for the steady-state serum concentrations ofN-acetyl-5-acetylsalicylic acid were greater in elderly than in young patients. The metabolism of sulfapyridine was markedly affected by acetylator phenotype and this was reflected in the composition of sulfapyridine-related material in the urine. Thus, age is a determinant of the steady-state concentrations of salicylate moieties but acetylator phenotype plays a greater role in determining the serum concentration of sulfapyridine, which has greater therapeutic implications in rheumatology.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS