Effect of acute and chronic exercise on hepatic drug metabolism

Recent research indicates that physical exercise and fitness are new host factors with impact on hepatic drug metabolism, contributing to the intra- and interindividual variation in drug response. Moderate to heavy physical exercise for a few hours reduces liver blood flow as assessed by indocyanine green clearance, leading to a decreased elimination of drugs exhibiting flow-limited metabolism (high clearance drugs) such as lignocaine (lidocaine). However, hepatic elimination of drugs exhibiting capacity-limited metabolism (low clearance drugs) such as antipyrine (phenazone), diazepam and amylobarbitone (amobarbital) is not affected by acute physical exercise. Improved physical fitness as expressed by the maximum oxygen uptake seems to increase the elimination rate of the low clearance drug antipyrine and possibly also aminopyrine, while investigations of the biotransformation of high clearance drugs are contradictory. The sum of research in this recent field is rather limited and the mechanism whereby changes in physical fitness influence hepatic drug metabolism needs to be established. It is not known if other liver functions are changed. If the findings also apply for drugs with a low therapeutic index, there may be a risk of exercise-induced changes in drug efficacy and toxicity. It is suggested that future studies on host factors influencing drug metabolism should include information on physical activity.     

Consequences of renal insufficiency on the hepatic clearance of some drugs

There have been numerous investigations into the effect of kidney or liver diseases on the renal or hepatic elimination of drugs, but little is known about the possible consequences of renal insufficiency on the hepatic clearance of medicinal agents. The first reports of diminished presystemic elimination of drugs in renal failure were presented by Bianchetti in 1976 for propranolol and by Levy in 1979 for dextropropoxyphene. We confirmed the fact that the hepatic presystemic elimination of drugs might be diminished by kidney diseases. We studied this phenomenon with the beta-blocking agents tolamolol, bufuralol and oxprenolol. Tolamolol is eliminated from the body mainly by aromatic hydroxylation and, for bufuralol, aliphatic hydroxylation also plays an important role, whereas, for oxprenolol, glucuroconjugation of the unchanged compound is an important route of elimination. After oral administration, the areas under the plasma/blood concentration curves were markedly increased in patients with renal insufficiency as compared to healthy subjects. The clearance approach of Rowland and Tozer led to the conclusion that decrease of the presystemic hepatic elimination might be the main reason for this finding. Cefoperazone is a cephalosporin eliminated to 75% by the biliary route under normal conditions. In a study in which the drug was intravenously infused to both healthy volunteers and patients with renal insufficiency, we found that in some patients the extrarenal clearance was markedly reduced. It is probable that in this situation the patients also suffered from a slight hepatic insufficiency, as sometimes observed in the case of kidney disease associated with a poor physical condition. It is well-known that in patients with terminal liver failure, the kidney may also be involved, producing a condition known as the "hepato-renal" syndrome. We feel that there is evidence to support the hypothesis that renal failure can disturb the pharmacokinetics of drugs by processes other than merely reducing their renal excretion. The precise causes of the decreased hepatic elimination found in renal patients remains, however, to be determined.     

Pharmacokinetics of drugs in overdose.

The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution may delay or broaden peak serum concentrations. The pathophysiological effects of a drug may also limit or augment absorption. Altered distribution of drugs in overdose results from changes in the extent of protein binding and size of the volume of distribution. Saturation of hepatic enzyme systems in overdose is manifested by delayed metabolism or elimination of many drugs; renal elimination of unchanged drug may take on greater importance in this instance. Familiarity with the toxicokinetic profile of a given drug enables the physician to exploit these principles in order to limit toxicity. Delayed or prolonged absorption allows for late decontamination. Multiple doses of activated charcoal are effective in interrupting both entero-enteric and enterohepatic recirculation. Alkalinisation-induced ion trapping enhances renal elimination of unchanged drugs which normally undergo hepatic transformation. For several drugs, chronic overdose due to altered distribution is associated with a greater severity of toxic manifestations despite relatively low serum drug concentrations. Conversely, with some drugs, induction of metabolic pathways may lead to more rapid drug elimination in chronic overdose. Knowledge of the pharmacokinetic alterations which occur in drug overdose enables the physician to predict toxicity with greater accuracy and to institute optimum therapy in a timely manner.     

Ontogeny of hepatic and renal systemic clearance pathways in infants: part I

Dramatic developmental changes in the physiological and biochemical processes that govern drug pharmacokinetics and pharmacodynamics occur during the first year of life. These changes may have significant consequences for the way infants respond to and deal with drugs. The ontogenesis of systemic clearance mechanisms is probably the most critical determinant of a pharmacological response in the developing infant. In recent years, advances in molecular techniques and an increased availability of fetal and infant tissues have afforded enhanced insight into the ontogeny of clearance mechanisms. Information from these studies is reviewed to highlight the dynamic and complex nature of developmental changes in clearance mechanisms in infants during the first year of life. Hepatic and renal elimination mechanisms constitute the two principal clearance pathways of the developing infant. Drug metabolising enzyme activity is primarily responsible for the hepatic clearance of many drugs. In general, when compared with adult activity levels normalised to amount of hepatic microsomal protein, hepatic cytochrome P450-mediated metabolism and the phase II reactions of glucuronidation, glutathione conjugation and acetylation are deficient in the neonate, but sulfate conjugation is an efficient pathway at birth. Parturition triggers the dramatic development of drug metabolising enzymes, and each enzyme demonstrates an independent rate and pattern of maturation. Marked interindividual variability is associated with their developmental expression, making the ontogenesis of hepatic metabolism a highly variable process. By the first year of life, most enzymes have matured to adult activity levels. When compared with adult values, renal clearance mechanisms are compromised at birth. Dramatic increases in renal function occur in the ensuing postpartum period, and by 6 months of age glomerular filtration rate normalised to bodyweight has approached adult values. Maturation of renal tubular functions exhibits a more protracted time course of development, resulting in a glomerulotubular imbalance. This imbalance exists until adult renal tubule function values are approached by 1 year of age. The ontogeny of hepatic biliary and renal tubular transport processes and their impact on the elimination of drugs remain largely unknown. The summary of the current understanding of the ontogeny of individual pathways of hepatic and renal elimination presented in this review should serve as a basis for the continued accruement of age-specific information concerning the ontogeny of clearance mechanisms in infants. Such information can only help to improve the pharmacotherapeutic management of paediatric patients.     

Disease-induced modifications of drug pharmacokinetics

This article attempts to help in the understanding of the mechanisms responsible for a modified drug pharmacokinetic profile in disease states. The main factors influencing the fate of the drug as it moves from the site of administration to the sites of elimination are depicted. Changes in absorption kinetics can be due to altered gastrointestinal peristalsis and secretions as well as modifications of splanchnic blood flow. Pathological states may affect the binding of drugs to plasma proteins, mainly human serum albumin and alpha 1 acid glycoprotein. The resulting modifications in the free fraction of the drug can cause a change in the volume of distribution. The distribution can also be influenced by circulatory disorders modifying local blood flows and thus impeding drug entry into the tissues. Many diseases can alter hepatic and/or renal clearance. This is not surprising since the elimination mechanisms are dependent upon many factors such the enzymatic status of the liver, plasma protein binding, and blood flow to both the liver and the kidney. Some examples such as the modification of furosemide pharmacokinetics in acute renal failure, the impaired metabolism of opiate analgesics in hepatic insufficiency, the alterations of the usual disposition process in salicylic acid intoxication, and the influence of cardiac failure upon some drugs pharmacokinetics, have been chosen to illustrate some of the aspects discussed. Some simple rules for making a rational selection of drugs in pathological states are also outlined.     

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.     

Selecting neuromuscular-blocking drugs for elderly patients

The physiological changes that occur with increasing age can have significant effects on the pharmacokinetics of neuromuscular-blocking drugs. Changes in cardiac output can affect drug distribution and therefore the speed of onset of neuromuscular block. A decrease in muscle mass and increase in body fat with age can also affect their distribution. The deterioration in renal and hepatic function associated with aging affects the clearance and elimination of many neuromuscular-blocking drugs. The effects of these physiological changes on the pharmacokinetics of neuromuscular-blocking agents may not become apparent clinically in healthy individuals until the age of at least 75 years. There is very little evidence to suggest any alteration in the sensitivity of the neuromuscular junction to neuromuscular-blocking drugs with increasing age. Neuromuscular-blocking drugs that undergo a significant degree of organ-dependent elimination, such as pancuronium bromide, vecuronium bromide, rocuronium bromide and doxacurium chloride, may have a significantly prolonged duration of action in elderly patients. These drugs can be used safely in elderly patients if the anaesthetist is aware of their altered pharmacokinetics in this patient group. Appropriate changes must be made to drug dosage and dose intervals. As the pharmacokinetic changes can be unpredictable, monitoring of neuromuscular block is strongly advised when using these drugs in such patients. The risk of residual block occurring postoperatively after the use of pancuronium bromide increases with age. The duration of action of mivacurium chloride may also be prolonged in the elderly; this change has not been demonstrated to be a result of an alteration in plasma cholinesterase activity. In contrast, there is no evidence of an alteration in the action of suxamethonium chloride (succinylcholine chloride) with increasing age. Atracurium besilate and cisatracurium besilate undergo predominantly organ-independent elimination. Onset of block with these two drugs may be prolonged in the elderly, but their clinical duration of action does not alter significantly with age, making them particularly suitable for use in this patient group. Although atracurium besilate may cause histamine release, there is little evidence of it producing haemodynamic changes in the elderly. Its (1R,1R')-isomer, cisatracurium besilate, has very little direct or indirect cardiovascular effect and is, therefore, the most suitable nondepolarising agent to use in elderly patients.     

The pharmacokinetics of perindopril and its effects on serum angiotensin converting enzyme activity in hypertensive patients with chronic renal failure.

1. Perindopril, an orally active angiotensin converting enzyme inhibitor, was given to 23 hypertensive patients with stable chronic renal failure for 15 days. The dose of perindopril was 2 or 4 mg once a day according to the degree of renal failure. The creatinine clearance of the patients ranged from 6 to 67 ml min-1 1.73 m-2. The pharmacokinetics of perindopril and perindoprilat, its active metabolite, were studied after acute and chronic administration of perindopril. 2. The drug was well tolerated and creatinine clearance was unaltered by treatment. 3. In both groups, steady-state was reached within 3 days of chronic treatment. 4. After both acute and chronic drug administration renal impairment had no effect on perindopril pharmacokinetics but the pharmacokinetics of perindoprilat were altered significantly. After chronic administration the serum accumulation ratio was 1.81 in patients with mild renal failure and 5.35 in patients with severe renal failure. Chronic administration did not modify the renal clearance of perindoprilat nor its elimination half-life. 5. A significant correlation between the renal clearance of perindoprilat and creatinine clearance was observed (r = 0.87 first dose, r = 0.83 last chronic dose). 6. A non-linear relationship between serum perindoprilat concentration and inhibition of angiotensin converting enzyme was described by a modified Hill equation. Values of IC50 were 1.11 +/- 0.07 micrograms I-1 (mean +/- s.d.) in patients with severe renal failure and 1.81 +/- 0.20 micrograms l-1 in patients with moderate renal failure. Chronic administration increased maximal inhibition and decreased the time to maximal inhibition only in patients with severe renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Up-regulation of renal Mdr1 and Mrp2 transporters during amiodarone pretreatment in rats

Although amiodarone (AMD) is known to produce drug–drug interactions through inhibition of transporter-mediated excretion of drugs, its impact on these mechanisms during chronic treatment has not been described yet. Therefore, the aim of this study was to investigate the influence of AMD pretreatment on the main multidrug transporting proteins, Mdr1 and Mrp2, in the liver and kidney. The expression of the transporters and pharmacokinetics of their substrates, rhodamine-123 (Rho123) and endogenous conjugated bilirubin (CB), were evaluated in rats after either AMD oral pretreatments (4–14 days) or single intravenous bolus. AMD pretreatment of all durations up-regulated renal Mdr1 and Mrp2 protein expression to 155–190% and 152–223% of the control values, respectively. In agreement, we observed a corresponding increase in renal clearance of both substrates. Hepatic expression was increased only for Mdr1 to 234–270% of controls, which was associated with increased biliary elimination of amiodarone without change in Rho123 biliary clearance. Interestingly, hepatic expression of another Mdr transporter, Mdr2, was progressively decreased by amiodarone administration. Acute administration of AMD reduced Rho123 biliary clearance by 64%. Our results indicate that repeated administration of AMD to rats is associated with significant increase in hepatic and renal expression of Mdr1 and Mrp2 transporters, which may contribute to variability in pharmacokinetics of AMD and simultaneously applied drugs.     

Effects of Long-Term Drugs on Alfentanil Clearance in Patients Undergoing Renal Transplantation

Although patients in renal failure frequently take several drugs on a long-term basis, drug-induced alterations in alfentanil metabolism have not been examined as a possible source of variability in alfentanil clearance in this population. We compared the pharmacokinetics of alfentanil during renal transplantation in seven patients receiving and six not receiving long-term drug therapy. After the rapid intravenous injection of alfentanil 100 μg/kg during isoflurane anesthesia, plasma concentrations were measured at intervals up to 6 hours by radioimmunoassay. The terminal elimination half-life, steady-state volume of distribution (Vd_ss), and total body clearance were determined by non-compartmental methods. There was no statistical difference in the Vd_ss between the two patient groups. However, clearance was significantly higher and elimination half-life lower in the group taking long-term drugs: clearance 6.94 ± 4.64 versus 3.47 ± 0.16 ml·kg⁻¹·min⁻¹, and elimination half-life 50.6 ± 13.9 versus 90.7 ± 22.4 minutes, respectively (p<0.05). The higher clearance occurred even though five of the seven patients were taking agents known to be metabolized by the same cytochrome P-450 hepatic isozyme that metabolizes alfentanil and therefore potential competitive inhibitors of alfentanil metabolism. Drugs taken by the three patients with the highest alfentanil clearances included known inducers of hepatic drug metabolism. Thus, in the presence of several long-term drugs, the clearance of alfentanil appears to be noticeably increased by inducers of hepatic drug metabolism but unaffected by potential competitive inhibitors.     

Clinical pharmacokinetics of the newer neuromuscular blocking drugs

The pharmacokinetics of 6 new neuromuscular blocking drugs are described. These are the aminosteroids pipecuronium bromide, rocuronium bromide and rapacuronium bromide (ORG-9487) and the benzylisoquinolinium diesters doxacurium chloride, mivacurium chloride and cisatracurium besilate. In healthy individuals, these drugs all have similar volumes of distribution. Their pharmacokinetics are influenced little by age or anaesthetic technique, but renal and hepatic disease may significantly alter their distribution and elimination. Pipecuronium resembles pancuronium in its pharmacokinetic and neuromuscular blocking profile, but is devoid of cardiovascular effects. It has a low clearance (0.16 L/h/kg) and long elimination half-life (120 minutes). It is largely eliminated through the kidney. Rocuronium has a similar pharmacokinetic profile to vecuronium but its onset of action is more rapid and duration of action slightly shorter. Its clearance (0.27 L/h/kg) is intermediate between those of pipecuronium and rapacuronium, but its elimination half-life is long (83 minutes). The pharmacokinetics of rocuronium are altered by renal and hepatic disease; the latter probably has the more significant effect. Rapacuronium has a rapid onset, and a bolus dose has a short duration of action. It has a high clearance (0.59 L/h/kg) but a long elimination half-life (112 minutes). Doxacurium has a pharmacokinetic and pharmacodynamic profile similar to pipecuronium. It has a high potency and is devoid of cardiovascular effects. In adults, it has a low clearance (0.15 L/h/kg) and long elimination half-life (87 minutes). Mivacurium is a mixture of 3 stereoisomers. It has a short to intermediate duration of action. It is hydrolysed by plasma cholinesterase. Inherited or acquired alterations in plasma cholinesterase activity are associated with changes in the pharmacokinetics and time course of action of mivacurium. The 2 active isomers (cis-trans and trans-trans) have a high clearance (4.74 L/h/kg) and very short elimination half-lives (approximately 2 minutes). Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. It has similar pharmacokinetics and pharmacodynamics to atracurium. It is mainly broken down by Hofmann (non-enzymatic) degradation. Cisatracurium has an intermediate clearance (0.3 L/h/kg) and short elimination half-life (26 minutes). Hepatic and renal disease have little effect on its pharmacokinetics.     

Quinolone disposition in the elderly. Practical implications.

The fluoroquinolones are antibiotics frequently used in infections that affect elderly individuals. The physiological aging process can profoundly affect the pharmacokinetics of drugs, necessitating adjustment of dosage regimens in the elderly. Changes in pharmacokinetics with age are mainly due to the progressive deterioration of renal function, with resultant lower clearance of drugs which are eliminated by the kidneys. Ofloxacin is almost totally renally excreted and elimination is slower in older age groups; a dose reduction is therefore recommended for this quinolone. Unexpected alterations in pharmacokinetics may occur, as exemplified by the increased bioavailability of oral ciprofloxacin in elderly subjects. This is a well-documented phenomenon of such significance that lower oral doses are advisable for the elderly. Renal clearance of ciprofloxacin decreases in old age, but because of substantial nonrenal elimination the total clearance is affected less. Studies of the pharmacokinetics of the other quinolones in old age are scarce. No data exist on the absolute oral bioavailability of norfloxacin, enoxacin and pefloxacin. Renal clearance seems to be reduced, but since no intravenous studies have been reported, the total and nonrenal clearances are unknown in the elderly. No safe conclusions can be drawn regarding the necessity of dose reductions from a pharmacokinetic point of view. However, reports of adverse reactions to quinolones in the elderly, especially concentration-dependent symptoms from the central nervous system, and the risk of interaction with other drugs, suggest the need for caution in determining dosages of all of these compounds in elderly subjects.     

Pharmacokinetics of calcium antagonists under development

Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs, amlodipine, has significant pharmacokinetic differences from the agents currently in use, although possible pharmacodynamic differences among the drugs have been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment.

The disposition of a single 20-mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration-time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half-life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P less than .001). The area under the serum concentration-time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single-dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.     

Effect of hepatic insufficiency on pharmacokinetics and drug dosing

The liver plays a central role in the pharmacokinetics of many drugs. Liver dysfunction may not only reduce the plasma clearance of a number of drugs eliminated by biotransformation and/or biliary excretion, but it can also affect plasma protein binding which in turn could influence the processes of distribution and elimination. In addition, reduced liver blood flow in patients with chronic liver disease will decrease the systemic clearance of flow limited (high extraction) drugs and portalsystemic shunting may substantially reduce their presystemic elimination (firstpass effect) following oral administration. When selecting a drug and its dosage regimen for a patient with liver disease additional considerations such as altered pharmacodynamics and impaired renal excretion (hepatorenal syndrome) of drugs and metabolites should also be taken into account. Consequently, dosage reduction is necessary for many drugs administered to patients with chronic liver disease such as liver cirrhosis.     

The effect of respiratory disorders on clinical pharmacokinetic variables

Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or antimicrobial agents in pulmonary disease. In patients under mechanical ventilation, the half-life of midazolam, a new benzodiazepine used as a sedative, has been found to be lengthened but the underlying mechanism is not well understood. Pulmonary absorption of pentamidine was found to be increased in patients under mechanical ventilation. Pharmacokinetic impairment does occur in patients with severe pulmonary disease but more work is needed to understand the exact mechanisms and to propose proper dosage regimens.     

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 antimicrobial drugs in cystic fibrosis.

The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight.     

Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age-related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.