摘要:

Famciclovir is an oral prodrug of the antiherpesvirus nucleoside analogue, penciclovir. Following oral administration famciclovir undergoes extensive first pass metabolism to penciclovir and essentially no parent compound is recovered from plasma or urine. Penciclovir plasma concentrations reach a maximum less than 1 hour after famciclovir administration in fasting individuals, but are delayed if famciclovir is taken within 2 hours of a meal. The bioavailability of penciclovir, measured by urinary recovery, is approximately 60% and is not affected by food. Over the likely therapeutic dose range of famciclovir 125mg to 750mg, the pharmacokinetics of penciclovir are linear.The volume of distribution of penciclovir after intravenous administration is more than 1 L/kg, indicating extensive distribution into the tissue. Penciclovir is predominantly eliminated unchanged by the kidney, partly by active tubular excretion and has a terminal phase elimination half-life (t½&bgr;) of between 2 and 2.5 hours and a renal clearance (CLR) of between 25 and 30 L/h in individuals with normal renal function. In those with severe renal impairment the CLRfalls markedly and the t½&bgr;increases to over 18 hours. Haemodialysis appears to be effective in clearing penciclovir from plasma.Elderly individuals tolerate famciclovir well, despite slower elimination secondary to age-related lower renal clearance. Uncomplicated herpes zoster does not affect the pharmacokinetic profile of penciclovir. In the limited studies undertaken so far, no significant drug interactions have been demonstrated.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

This review updates and evaluates the currently available information regarding the pharmacokinetics, metabolism and interactions of the acid pump inhibitors omeprazole, lansoprazole and pantoprazole. Differences and similarities between the compounds are discussed.Omeprazole, lansoprazole and pantoprazole are all mainly metabolised by the polymorphically expressed cytochrome P450 (CYP) isoformS-mephenytoin hydroxylase (CYP2C19), which means that within a population a few individuals (3% of Caucasians) metabolise the compounds slowly compared with the majority of the population. For all 3 compounds, the area under the plasma concentration-versus-time curve (AUC) for a slow metaboliser is, in general, approximately 5 times higher than that in an average patient. Since all 3 compounds are considered safe and well tolerated, and no dosage-related adverse drug reactions have been identified, this finding seems to be of no clinical relevance.The acid pump inhibitors seem to be similarly handled in the elderly, where a somewhat slower elimination can be demonstrated compared with young individuals. In patients with renal insufficiency, omeprazole is eliminated as in healthy individuals, whereas the data on lansoprazole and pantoprazole are unresolved. In patients with hepatic insufficiency, as expected, the elimination rates of all 3 compounds are substantially decreased.No clinically relevant effects on specific endogenous glandular functions, such as the adrenal (cortisol), the gonads or the thyroid, were demonstrated for omeprazole and pantoprazole, whereas a few minor concerns have been raised regarding lansoprazole.The absorption of some compounds, e.g. digoxin, might be altered as a result of the increased gastric pH obtained during treatment with acid pump inhibitors, and, accordingly, similar effects are expected irrespective of which acid pump inhibitor is given.The effect of the acid pump inhibitors on enzymes in the liver has been intensely debated, and some authors have claimed that lansoprazole and pantoprazole have less potential than omeprazole to interact with other drugs metabolised by CYP. However, after assessment of available data in this area, the conclusion is that all 3 acid pump inhibitors have a very limited potential for drug interactions at the CYP level. In addition, the small effects on CYP reported for these compounds are rarely of any clinical relevance, considering the normal intra- (and inter-)individual variations in metabolism observed for most drugs.In conclusion, omeprazole, lansoprazole and pantoprazole are structurally very similar, and an evaluation of available data indicates that also with respect to pharmacokinetics, metabolism and interactions in general they demonstrate very similar properties, even though omeprazole has been more thoroughly studied with regard to different effects.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Following the introduction of felbamate, gabapentin, lamotrigine, oxcarbazepine and vigabatrin in the early 1990s, other new antiepileptic drugs have been advancing in clinical development. Those most extensively evaluated to date include topiramate, zonisamide and tiagabine.Topiramate, licensed recently in the UK, acts multifactorially through the blockade of sodium channels and kainate/AMPA receptors, enhancement of &ggr;-aminobutyric acid (GABA)ergic transmission and inhibition of carbonic anhydrase. It is well absorbed from the gastrointestinal tract and negligibly bound to plasma proteins. When used as a monotherapy, topiramate is eliminated primarily in the urine in an unchanged form with a half-life of 20 to 30 hours; elimination is faster in patients receiving concurrent medication with enzyme-inducing anticonvulsants, in whom the extent of biotransformation becomes more prominent.Zonisamide, which has been commercially available in Japan for some years, also has a multifactorial mode of action, possibly involving the blockade of sodium channels, T-type calcium channels and inhibition of carbonic anhydrase. It is rapidly absorbed, 50% bound to plasma proteins and is eliminated predominantly by biotransformation; zonisamide has a half-life of 50 to 70 hours in monotherapy patients, or 25 to 35 hours in patients comedicated with enzymeinducing anticonvulsants.Tiagabine, a nipecotic acid derivative which inhibits GABA reuptake, is rapidly and completely absorbed after oral intake. It is highly (96%) bound to plasma proteins and it is eliminated primarily by cytochrome P450 3A-mediated oxidation, with a half-life of about 7 hours in healthy volunteers. Tiagabine metabolism is also enhanced by concurrent medication with enzyme-inducing anticonvulsants, resulting in a need to use dosages larger than those required in monotherapy or valproic acid (sodium valproate)-treated patients.Additional investigational antiepileptic agents included in this article are rufinamide (CGP 33101), fosphenytoin, levetiracetam, losigamone, remacemide and stiripentol. All these drugs have undergone early characterisation with respect to pharmacokinetic features and interaction potential.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Genetic and environmental factors contribute to a wide inter- and intraindividual variability in drug metabolism. Among the environmental factors that may influence drug metabolism, the diet and nutritional status of the individuals are important determinants. As altered drug-metabolising enzyme activities can influence the intensity and duration of drug action, such factors should be considered in pharmacotherapy. For this reason the effects of dietary energy, protein deficiency, nutritional ingredients, special diet forms and nutrition regimens and malnutritional states must be differentiated.In various pharmacokinetic studies different model drugs metabolised either by oxidative phase I pathways [e.g. phenazone (antipyrine), aminopyrine, phenacetin, theophylline, propranolol, nifedipine] or phase II conjugation reactions [e.g. paracetamol (acetaminophen), oxazepam] were used and from the calculated pharmacokinetic data some information on the involved and affected drug-metabolising enzymes [e.g. cytochrome P450 (CYP) subspecies, glucuronosyltransferases] can be generated. It is well known that smoking, charcoal broiled food or cruciferous vegetables induce the metabolism of many xenobiotics, whereas grapefruit juice increases the oral bioavailability of the high clearance drugs nifedipine, nitrendipine or felodipine by inhibiting their presystemic (intestinal) elimination. Energy deficiency, and especially a low intake of protein, will cause a decrease of about 20 to 40% in phenazone and theophylline clearance and elimination of those drugs can be accelerated by a protein-rich diet. In the same way, protein deficiency induced by either vegetarian food or undernourishment will have the opposite pharmacokinetic consequences. On the basis of some more examples from the literature it is emphasised that the variable influence of the above factors should be taken into account in study participant selection and study design when the pharmacokinetics of a drug must be determined in healthy individuals and/or patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Rapid drug delivery (arterial ‘boli’) and high drug concentrations occur with nicotine inhaled in smoke. These are believed to be key elements in producing addiction to cigarettes. Preparations which reduce the rate of delivery and/or concentration of nicotine have been introduced as treatments for smoking cessation.These nicotine medications work by relieving withdrawal and preventing relapse associated with abrupt cessation of smoking. The pharmacokinetics of each system are expected to affect efficacy and treatment dependence. Nasal administration systems have been developed to more closely approximate cigarette delivery for improved efficacy in clinical application and for more control in systematic testing of nicotine. With laboratory tested nasal application systems (clinical drug and experimental devices), venous plasma concentrations after a single dose range between 5 and 12 μg/L.Higher steady-state blood nicotine concentrations (16 to 29 μg/L) have been reported forad libitumclinical self-administration with a nicotine nasal spray. Time to peak plasma concentration (tmax) with nasal administration is around 11 to 13 minutes for 1mg doses. This rise time is slower than for cigarette delivery but faster than the other nicotine treatments. Venous plasma concentrations are considerably lower than tobacco product concentrations and fall within the range of the lower dose nicotine treatments (e.g. 2mg gumvs4mg gum).The profile of nasal nicotine administration was designed for certain subsets of smokers. Efficacy trials show consistent superiority of nasal administration over placebo although the comparative efficacy among nicotine treatments remains to be determined. The more rapid onset and user control of nasal nicotine may impose a higher risk for treatment dependence compared with a slower, passive system such as the patch. It may not produce more dependence than other faster-acting treatment systems (e.g. nicotine gum).

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS