ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The pharmacokinetics of chenodeoxycholic and ursodeoxycholic acids are reviewed in this article. Chenodeoxycholic acid is well absorbed by the intestine, whereas the absorption of ursodeoxycholic acid is incomplete. They are extracted efficiently by the liver, conjugated with glycerine and taurine, secreted in bile, and then undergo enterohepatic circulation with the endogenous bile acids. Therapeutic bile acids are metabolised by intestinal bacteria to lithocholic acid which is mainly excreted with faeces.Since the large majority of bile acid is confined within the enterohepatic circulation (resulting in low serum concentrations) their volume of distribution is relatively high. Despite the high hepatic extraction, the clearance of therapeutic bile acids is relatively low because of the highly efficient enterohepatic recirculation. Elimination of therapeutic bile acids mainly occurs in the faeces either unmodified or after biotransformation.At present the main clinical indication for therapeutic bile acids is ursodeoxycholic acid treatment for chronic cholestatic liver disease. In these patients, ursodeoxycholic acid is efficiently absorbed but its hepatic uptake and biliary secretion are impaired, thus leading to reduced biliary enrichment and high serum concentrations of this exogenous bile acid. In patients with cystic fibrosis-associated liver disease, bile acid malabsorption also occurs, thus indicating the need for higher dosages.The volume of distribution and clearance of ursodeoxycholic acid reduced in the presence of liver disease, Also in this case, elimination mainly occurs with the faeces but, in the presence of severe cholestasis, renal clearance may become relevant. Sulphation or conjugation with glucose andN-acetylglucosamine facilitate urinary excretion.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Considerable renewal of interest in this drug has been observed in recent years.Metformin can be determined in biological fluids by various methods, mainly using high performance liquid chromatography, which allows pharmacokinetic studies in healthy volunteers and diabetic patients. Metformin disposition is apparently unaffected by the presence of diabetes and only slightly affected by the use of different oral formulations.Metformin has an absolute oral bioavailability of 40 to 60%, and gastrointestinal absorption is apparently complete within 6 hours of ingestion. An inverse relationship was observed between the dose ingested and the relative absorption with therapeutic doses ranging from 0.5 to 1.5g, suggesting the involvement of an active, saturable absorption process. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identified. The absence of liver metabolism clearly differentiates the pharmacokinetics of metformin from that of other biguanides, such as phenformin.Metformin undergoes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This elimination is prolonged in patients with renal impairment and correlates with creatinine clearance.There are only scarce data on the relationship between plasma metformin concentrations and metabolic effects. Therapeutic levels may be 0.5 to 1.0 mg/L in the fasting state and 1 to 2 mg/L after a meal, but monitoring has little clinical value except when lactic acidosis is suspected or present. Indeed, when lactic acidosis occurs in metformin-treated patients, early determination of the metformin plasma concentration appears to be the best criterion for assessing the involvement of the drug in this acute condition. After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or haemodialysis, both of which favour rapid elimination of the drug. Although serious, lactic acidosis due to metformin is rare and may be minimised by strict adherence to prescribing guidelines and contraindications, particularly the presence of renal failure.Finally, only very few drug interactions have been described with metformin in healthy volunteers. Plasma levels may be reduced by guar gum and &agr;-glucosidase inhibitors and increased by cimetidine, but no data are yet available in the diabetic population.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t½) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight.Single-dose studies (1,2 and 4mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4mg 4 times daily for 4 weeks) do not show any accumulation of the drug.A study in young and elderly individuals indicated that the first-pass effect is decreased and t½prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds.A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life.The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile.Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised.Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentrations of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir.Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated.No interaction has been demonstrated with didanosineper sebut care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine.Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid ‘Maalox’ results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated.Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved.Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS