摘要:

Acyclovir is a selective anti-herpes virus agent. At present it is available in topical and intravenous formulations; an oral formulation is currently being developed.Absorption of acyclovir after oral administration is slow, variable and incomplete. The bioavailability of oral acyclovir is low and decreases with increasing dosage. The average time to peak concentrations is approximately 2 hours and achievable peak concentrations following oral administration (600mg every 4 hours) are less than 6 μmol/L with current oral dosage forms.Acyclovir tissue and fluid concentrations can be determined accurately and sensitively by high-performance liquid chromatography, radioimmunoassay, and by virus inhibition (bioassay). Acyclovir demonstrates biexponential elimination, with a terminal plasma halflife of 2 to 3 hours in patients with normal renal function. The volume of the central compartment (21 L/1.73m2) and the apparent volume of distribution at steady-state (48 L/1.73m2) are approximately that of extracellular fluid and total body water, respectively. The drug is distributed into all tissues, with concentrations in the kidney being the highest (10 times the simultaneous plasma concentration) and in central nervous tissue the lowest (25 to 70% of the corresponding plasma concentration). Acyclovir enters the cerebrospinal fluid, saliva and vaginal secretions at concentrations inhibitory to herpes simplex virus. The drug is poorly protein bound, in the range of 9 to 22%.Acyclovir is eliminated mainly via the kidney by glomerular filtration and renal tubular secretion, with only a small percentage of the dose being oxidised to 9-carboxymethoxymethylguanine (which is the only significant metabolite of acyclovir in man). Acyclovir has dose-independent kinetics. The renal clearance of acyclovir is about 75 to 80% of the total body clearance and approximately 3-fold greater than creatinine clearance. Probenecid reduces acyclovir renal clearance by 32%, presumably by inhibiting tubular secretion of the drug.In anuric patients, acyclovir is slowly eliminated with a terminal plasma half-life of approximately 20 hours. The acyclovir total body clearance (29 ml/min/1.73m2) is only 10% of that seen in patients without renal impairment. Acyclovir is readily haemodialysable with an extraction coefficient of 0.45 and a dialysis clearance of 82 ml/min using a hollow fibre single-pass dialyser. A single haemodialysis (6h) reduces acyclovir concentrations by 60%.The pharmacokinetics of acyclovir in children (greater than 1 year of age) are similar to those in adults. In neonates, the total body clearance is about one-third of that found in children and adults. The terminal plasma half-life is slightly longer in the neonate.The toxicity of acyclovir appears to be minimal and consists of local irritation after extravasation, phlebitis, and occasionally reversible elevations in serum creatinine, especially after intravenous bolus doses. Other adverse effects remain to be established. Acyclovir plasma concentrations of 50 to 100 μmol/L are easily achievable by slow intravenous administration without significant adverse effects. Dosage reduction is recommended in patients with impaired renal function, in order to achieve effective concentrations without concomitant drug accumulation.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The quantitative aspects of drug disposition in man of the commonly used antineoplastic agents, including cyclophosphamide, the nitrosoureas, cisplatin, methotrexate, cytarabine, 5-fluorouracil, doxorubicin, daunorubicin, bleomycin, vincristine, vinblastine, and vindesine are reviewed. Although the pharmacokinetic behaviour of these drugs has been adequately described in man, the chemical reactivity, the complexity of metabolism and disposition, the lack of simple, rapid and sensitive assays to measure plasma concentration, and the lack of defined therapeutic and toxic plasma concentrations have limited the application of routine drug monitoring in clinical oncology. With the exception of high dose methotrexate, drug doses and administration schedules remain empirical with a standard starting dose and subsequent dosage modifications determined by ensuing drug toxicities. However, many of the pharmacological characteristics of the drugs, such as their low therapeutic index, potentially life-threatening toxicities and wide individual variability in drug disposition, necessitate pharmacological monitoring.Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction. Consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

New benzodiazepine derivatives continue to be developed and introduced into clinical use. The pharmacokinetic properties of these newer drugs can best be understood by their categorisation according to range of elimination half-life and pathway of metabolism (oxidation versus conjugation). Clobazam and halazepam are long half-life (and therefore accumulating) anxiolytics metabolised by oxidation. Alprazolam and clotiazepam also are oxidised compounds but have short to intermediate half-life values and therefore produce considerably less accumulation. Temazepam and lormetazepam are hypnotic agents with intermediate half-lives but metabolised by conjugation. The most unique of the newer benzodiazepines are the ultra-short half-life (oxidised) compounds midazolam, triazolam and brotizolam, which are essentially non-accumulating during multiple dosage.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Propranolol is widely used in clinical practice and is frequently administered along with other drugs. The co-administration of propranolol and other drugs may result in either propranolol-induced changes in the disposition of other drugs or in effects of the other drugs on the pharmacokinetics of propranolol. These changes may be due to alteration in absorption, metabolism or to haemodynamic effects such as altered liver blood flow.Understanding the pharmacokinetics of propranolol is important to the rational interpretation of the effects of other drugs on propranolol's disposition. The absorption, protein binding and metabolism of propranolol may all be affected by the co-administration of other drugs. Induction of propranolol's metabolism by halofenate, phenytoin, phenobarbitone, rifampicin and alcohol have all been implicated in altering propranolol clearance, while inhibition of hepatic drug metabolising enzymes by chlorpromazine and cimetidine appear to reduce propranolol clearance.Propranolol may also affect the metabolism of other drugs such as antipyrine, chlorpromazine, theophylline and thyroid hormones. Suggestions that propranolol may alter quinidine's elimination have not been substantiated. By reducing liver blood flow propranolol may reduce the systemic clearance of other high extraction drugs such as lignocaine.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Average steady-state serum salicylate concentrations and salicyluric acid (SU) formation rates were measured in 4 subjects with rheumatoid arthritis. After a salicylate washout period (1 month), the mean observed maximum formation rate of SU was determined by collecting frequent urine samples after a single oral dose of salicylate (35 mg/kg). The patients were then commenced on appropriate high dose salicylate therapy. Two and 5 weeks later, the mean observed maximum rates of SU formation were re-determined along with the average steady-state serum salicylate concentrations. Mean observed maximum SU excretion rates increased significantly between the single-dose study (0.96 ± 0.22 mg/kg/h) and the last dose of the high dose therapy at 2 weeks (1.65 ± 0.30 mg/kg/h; p < 0.01); however, there was no further increase at week 5. Similar increases in the theoretical maximum rate of SU formation (Vmax) were observed between the single-dose study and after 2 weeks of high dose salicylate therapy. Average steady-state serum salicylate concentrations showed no decline between weeks 2 and 5.High dose salicylate therapy leads to acceleration of the rate of SU formation in patients with rheumatoid arthritis and this occurs largely during the first 2 weeks of therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The pharmacokinetics of phenylethylmalonamide (PEMA), one of the major metabolites of the antiepileptic drug primidone, have been studied in 6 healthy volunteers after administration of single 500mg intravenous and oral doses. Following intravenous administration, after a very short distributive phase (t1/2= 0.23-0.53h), the decline of the log-PEMA concentration with respect to time appeared linear. The pharmacokinetic parameters, calculated according to a 1-compartment open model, showed the following values (mean ± SD): terminal half-life, 15.7 ± 3.4h; apparent volume of distribution, 0.69 ± 0.10 L/kg; total serum clearance, 31.3 ± 6.6 ml/h/kg.After oral administration, peak serum concentrations occurred at 0.5 to 4 hours and the oral bioavailability was 86.4 to 95.9%.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS