Dose adjustment in patients with liver disease.

Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.     

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.     

Analgesics in patients with hepatic impairment: pharmacology and clinical implications

The physiological changes that accompany hepatic impairment alter drug disposition. Porto-systemic shunting might decrease the first-pass metabolism of a drug and lead to increased oral bioavailability of highly extracted drugs. Distribution can also be altered as a result of impaired production of drug-binding proteins or changes in body composition. Furthermore, the activity and capacity of hepatic drug metabolizing enzymes might be affected to various degrees in patients with chronic liver disease. These changes would result in increased concentrations and reduced plasma clearance of drugs, which is often difficult to predict. The pharmacology of analgesics is also altered in liver disease. Pain management in hepatically impaired patients is challenging owing to a lack of evidence-based guidelines for the use of analgesics in this population. Complications such as bleeding due to antiplatelet activity, gastrointestinal irritation, and renal failure are more likely to occur with nonsteroidal anti-inflammatory drugs in patients with severe hepatic impairment. Thus, this analgesic class should be avoided in this population. The pharmacokinetic parameters of paracetamol (acetaminophen) are altered in patients with severe liver disease, but the short-term use of this drug at reduced doses (2 grams daily) appears to be safe in patients with non-alcoholic liver disease. The disposition of a large number of opioid drugs is affected in the presence of hepatic impairment. Certain opioids such as codeine or tramadol, for instance, rely on hepatic biotransformation to active metabolites. A possible reduction of their analgesic effect would be the expected pharmacodynamic consequence of hepatic impairment. Some opioids, such as pethidine (meperidine), have toxic metabolites. The slower elimination of these metabolites can result in an increased risk of toxicity in patients with liver disease, and these drugs should be avoided in this population. The drug clearance of a number of opioids, such as morphine, oxycodone, tramadol and alfentanil, might be decreased in moderate or severe hepatic impairment. For the highly excreted morphine, hydromorphone and oxycodone, an important increase in bioavailability occurs after oral administration in patients with hepatic impairment. Lower doses and/or longer administration intervals should be used when these opioids are administered to patients with liver disease to avoid the risk of accumulation and the potential increase of adverse effects. Finally, the pharmacokinetics of phenylpiperidine opioids such as fentanyl, sufentanil and remifentanil appear to be unaffected in hepatic disease. All opioid drugs can precipitate or aggravate hepatic encephalopathy in patients with severe liver disease, thus requiring cautious use and careful monitoring.     

Antiarrhythmics: elimination and dosage considerations in hepatic impairment

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index. The present review summarises the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal. The hepatically eliminated antiarrhythmics are metabolised mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics. In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.     

细胞毒性药物在肝肾功能不全患者中的剂量调整

目的：探索细胞毒性药物在肝肾功能不全患者中的剂量调整。方法：以"细胞毒性药物","肝功能不全","肾功能不全"为关键词对Pubmed,EMbase,Cochrane Library,中国知网,万方,维普等数据库进行检索,以整理和归纳细胞毒性药物在肝肾功能不全患者中的剂量调整策略。结果：肝肾功能不全可影响药物的代谢动力学,进而影响药物的安全性和有效性。45种常见细胞毒性药物,当肝功能不全时,有41种药物需要进行剂量调整;当肾功能不全时,有33种药物需要进行剂量调整。结论：应重视细胞毒性药物在肝肾功能不全患者中的剂量调整,以保障患者用药的安全性和有效性。     

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease

Summary A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250 mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.     

Pharmacokinetics and drug metabolism in the elderly

Aging involves progressive impairments in the functional reserve of multiple organs, which might also affect drug metabolism and pharmacokinetics. In addition, the elderly population will develop multiple diseases and, consequently, often has to take several drugs. As the hepatic first-pass effect of highly cleared drugs could be reduced (due to decreases in liver mass and perfusion), the bioavailability of some drugs can be increased in the elderly. Significant changes in body composition occur with advancing age. Lipophilic drugs may have an increased volume of distribution (Vd) with a prolonged half-life, and water-soluble drugs tend to have a smaller Vd. In the elderly, hepatic drug clearance of some drugs can be reduced by up to 30% and CYP-mediated phase I reactions are more likely to be impaired than phase II metabolism, which is relatively preserved in the elderly. Concerning the most important CYP3A4 studies with human liver microsomes and clinical studies with the validated probe, midazolam, it is indicated that there are no significant differences in CYP3A4 activity between young and old populations. Finally, renal excretion is decreased (up to 50%) in about two thirds of elderly subjects, but confounding factors such as hypertension and coronary heart disease account also for a decline in kidney function. In conclusion, age-related physiological and pharmacokinetic changes as well as the presence of comorbidity and polypharmacy will complicate drug therapy in the elderly.     

Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events

Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.     

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment

IntroductionIn December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing.MethodsCOVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website (www.covid19-druginteractions.org), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases.FindingsRemdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities.ConclusionDosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.     

Kinetic impact of presystemic intestinal metabolism on drug absorption: experiment and data analysis for the prediction of in vivo absorption from in vitro data

Orally administered drugs suffer from attack by metabolic enzymes not only in the liver, but also in the gastrointestine during the absorption process across the intestinal tissue. Although kinetic study on hepatic metabolism has been done well, the intestinal metabolism has not been well focused on compared with hepatic metabolism. In order to emphasize the role of intestinal metabolism in drug absorption and bioavailability, I have reviewed the experimental methods for intestinal absorption and metabolism, and the data analysis. Since Klippert et al. reported the prediction of intestinal first-pass effect of phenacetin in the rat from enzyme kinetic data in 1982, several reports have showed a good prediction, but others have not. Although intestinal absorption is an integrated process of transport (transporters) and metabolism (metabolic enzymes), most of the researchers missed the pathway of intestinal drug absorption and applied the kinetic model effective on only systemic metabolism to presystemic intestinal metabolism for their analysis of intestinal metabolism of orally administered drugs. A kinetic model, which incorporated factors of membrane transport, metabolic activity and protein binding, was structured to compare the equations in the reported models. In conclusion, we need more studies including kinetic modeling and experiments to understand the impact of intestinal metabolism on drug absorption. That knowledge must lead to the construction of ADME in silico (e-ADME).     

Impaired maraviroc and raltegravir clearance in a human immunodeficiency virus-infected patient with end-stage liver disease and renal impairment: a management dilemma

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189?hours for maraviroc and 61?hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18?hours and 9-12?hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48?hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.     

Cimetidine as an inhibitor of drug metabolism: therapeutic implications and review of the literature

Cimetidine has been reported to decrease the biotransformation of drugs metabolized by the MFOE system. Additionally, cimetidine decreases liver blood flow and increases the bioavailability of drugs with high hepatic extraction ratios. Patients receiving cimetidine in conjunction with drugs known to interact with cimetidine in conjunction with drugs known to interact with cimetidine are at risk of experiencing toxicity. When appropriate, reducing the dosage of these agents or switching to an alternative drug will minimize the incidence of side effects. Clinicians should be suspicious if patients experience exaggerated drug effects when cimetidine therapy is begun.     

Effects of liver disease on pharmacokinetics. An update

Liver disease can modify the kinetics of drugs biotransformed by the liver. This review updates recent developments in this field, with particular emphasis on cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharmacology. The information currently available on specific isoforms involved in drug metabolism has increased tremendously over the latest years, but knowledge remains incomplete. Studies on the effects of liver disease on specific isoenzymes of CYP have shown that some isoforms are more susceptible than others to liver disease. A detailed knowledge of the particular isoenzyme involved in the metabolism of a drug and the impact of liver disease on that enzyme can provide a rational basis for dosage adjustment in patients with hepatic impairment. The capacity of the liver to metabolise drugs depends on hepatic blood flow and liver enzyme activity, both of which can be affected by liver disease. In addition, liver failure can influence the binding of a drug to plasma proteins. These changes can occur alone or in combination; when they coexist their effect on drug kinetics is synergistic, not simply additive. The kinetics of drugs with a low hepatic extraction are sensitive to hepatic failure rather than to liver blood flow changes, but drugs having a significant first-pass effect are sensitive to alterations in hepatic blood flow. The drugs examined in this review are: cardiovascular agents (angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antagonists, ketanserin, antiarrhythmics and hypolipidaemics), diuretics (torasemide), psychoactive and anticonvulsant agents (benzodiazepines, flumazenil, antidepressants and tiagabine), antiemetics (metoclopramide and serotonin antagonists), antiulcers (acid pump inhibitors), anti-infectives and antiretroviral agents (grepafloxacin, ornidazole, pefloxacin, stavudine and zidovudine), immunosuppressants (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene. According to the available data, the kinetics of many drugs are altered by liver disease to an extent that requires dosage adjustment; the problem is to quantify the required changes. Obviously, this requires the evaluation of the degree of hepatic impairment. At present there is no satisfactory test that gives a quantitative measure of liver function and its impairment. A critical evaluation of these methods is provided. Guidelines providing a rational basis for dosage adjustment are illustrated. Finally, it is important to consider that liver disease not only affects pharmacokinetics but also pharmacodynamics. This review also examines drugs with altered pharmacodynamics.     

Calcium antagonists. Pharmacokinetic properties

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.     

13C-breath tests in the study of mitochondrial liver function

Breath tests for "dynamic" liver function evaluation have been proposed several years ago. A variety of carbon-labelled breath tests for the assessment of mitochondrial, microsomal and cytosolic liver function have been described with the aim to increase data on liver disease staging, prognosis, and response to therapy. In the last years a great interest is developed about the use of breath test for liver mitochondrial function evaluation since it results impaired in a wide range of liver diseases either of genetic or acquired origin. In these cases mitochondrial oxidative metabolism of some substrates, as far as recovery of the hepatic energy state after a metabolic insult, results impaired because of the disfunction of the electron transport chain and/or ATP synthesis. Ketoisocaproic acid and methionine are the best studied carbon-labelled substrates for the investigation of mitochondrial functional damages related to structural alterations that occur in many liver diseases. Although these tests are simple, cost-effective and safe, to date there is still not general approval for their usefulness in clinical settings since they should fulfill several requirements to overcome the drawbacks of traditional quantitative tests. On the other hand, this field is relatively young and further studies are needed in order to assess the suitable substrate for the evaluation of the complex mitochondrial metabolism both in healthy subjects and in patients with liver disease.     

69例药物性肝炎的临床分析

目的:探讨药物性肝炎的临床特点.方法:回顾分析了2006～2011年收治的69例确诊为药物性肝炎患者的临床资料.结果:引起药物性肝炎的常见药物是中草药、抗结核药、抗生素、抗肿瘤药等.结论:引起药物性肝炎的药物种类多,许多临床常见的药物可引起肝脏损害,应加强临床用药指导及药物性肝炎的防治.     

Dose-dependent bioavailability of prazosin in beagle dogs

Prior to the introduction of an intravenous dosage form for use in humans, prazosin pharmacokinetic studies emphasizing clearance, hepatic extraction, and bioavailability were carried out in dogs. Two such canine studies reported significantly different values for the oral bioavailability of prazosin. This study investigated the differences in prazosin oral availability in beagle dogs. Three male animals were administered an intravenous (1 mg/kg) and three different oral doses (15, 5, and 1 mg) with a 7-day washout between study days. The mean predicted bioavailability, based on hepatic clearance and an estimate for liver blood flow, was 74%. The mean absolute bioavailabilities, determined for each dose in each animal by comparing dose-corrected areas under the plasma concentration-time curve, were 82, 27, and 23%. Although good agreement was evident in bioavailability between the 15-mg oral dose and what was predicted, calculated availabilities for the 5-mg and 1-mg oral doses were approximately one-third the predicted value. The results obtained from this study, together with data from the two previous studies, indicate that the bioavailability of prazosin in dogs is dose-dependent. Possible mechanisms for this observation are also presented.