The relationship between the pharmacokinetics and pharmacodynamic effects of oral hypoglycaemic drugs

Oral hypoglycaemic drugs have widely differing pharmacokinetic properties. Possible pharmacodynamic benefits include greater efficacy and fewer adverse effects. In general, it has not been possible to demonstrate unequivocal differences in clinical efficacy between the sulphonylureas during long term use, although there are clear differences in potency. These differences have been emphasised to the extent that the term 'second-generation' has been used for the most potent sulphonylureas, but there is little to suggest that potency is of any therapeutic significance. Trials to study differences in efficacy have rarely been of acceptable design. They have often used fixed doses of drugs, begging the question of whether true potency ratios have been established for chronic treatment. They have rarely involved substantial numbers of patients in double-blind crossover studies with a suitable washout period. Trials which show that there is a clear relationship between drug concentrations in blood and drug effects (whether therapeutic effects or adverse effects such as severe hypoglycaemia) are generally lacking. Qualitative and semiquantitative analysis of adverse effects supports the concept that drugs with a long half-life (e.g. chlorpropamide), renally excreted active metabolites (e.g. acetohexamide) or unusual properties (e.g. glibenclamide, which accumulates progressively in islet tissue) are more likely to cause prolonged hypoglycaemia, which may be fatal. The major adverse effect of treatment with biguanides is lactic acidosis, and this probably occurs more commonly in patients treated with phenformin than those treated with metformin because of pharmacogenetic variation in phenformin metabolism. The available evidence therefore favours the use of drugs with a short elimination half-life which are extensively metabolised and which have no active metabolites.     

Predictability of the effects of race or ethnicity on pharmacokinetics of drugs

The International Conference on Harmonization has put forth a tripartite guideline addressing mechanisms by which regulatory agencies might be able to accept foreign clinical data. A major issue is the effect of ethnicity on the drug's pharmacokinetics, pharmacodynamics and/or safety. The purpose of this review was to determine whether the effects of ethnicity on pharmacokinetics are predictable. We also evaluated whether the premise that only pharmacokinetic processes which are biologically or biochemically mediated are likely to exhibit ethnic differences was supported by the literature. Bioavailability is determined by absorption, gut metabolism/transport and hepatic first pass metabolism. Absorption is usually a passive process and, as would be expected, no examples of ethnic differences in passive absorption were found in the literature. Direct evaluation of ethnic differences in gut metabolism/transport or hepatic first pass metabolism is largely lacking, although some studies suggest such differences exist. These differences would also be expected based on known ethnic differences in hepatic clearance of drugs. Ethnic differences in plasma protein-binding to the two major drug-binding proteins, alpha1-acid glycoprotein (AGP) and albumin, have been studied in several populations. Based on these studies, ethnic differences in plasma protein-binding for drugs which bind exclusively to albumin (e.g. acids) are uncommon. Conversely, ethnic differences in plasma protein-binding of drugs to AGP appear to be very common, with the studies consistently showing Caucasians have higher binding (lower plasma free fractions) than other ethnic groups. This difference appears, in all cases, to be explained by racial differences in plasma AGP concentration. Hepatic metabolism is the most common pharmacokinetic parameter for which there are ethnic differences. Differences have been documented in both oxidative and conjugative metabolism. Ethnic differences in hepatic metabolism are unpredictable by race (e.g. one racial group is not consistently higher or lower than another group) and specific enzyme (e.g. studies with different CYP3A4 substrates have yielded different results). Ethnic differences in renal tubular secretion have been documented, but also appear to be unpredictable, while differences in the passive processes of renal elimination, filtration and reabsorption, have not been observed. The literature supports the premise that pharmacokinetic processes which are active (e.g. involve a protein) are the ones with the potential for differences between ethnic groups while passive pharmacokinetic processes do not exhibit such differences. Based on the available literature, the drugs most likely to exhibit ethnic differences in their pharmacokinetics are those that undergo significant gut metabolism/transport and/or hepatic first pass metabolism; are highly bound to plasma proteins (especially AGP); or have hepatic metabolism as a major route of elimination.     

The pharmacokinetics of antofloxacin in renally impaired rats

Our aim was to investigate whether renal impairment induced by cisplatin altered the pharmacokinetics of antofloxacin. Antofloxacin (7.5 mg kg(-1), i.v.) was given to normal or renally impaired rats (induced by cisplatin). Concentrations of antofloxacin in plasma and urine were measured using HPLC. Pharmacokinetic parameters were estimated. The plasma concentrations of antofloxacin in the renally impaired rats were significantly higher than those in the normal rats, accompanied by significant increase of the area under the plasma concentration-time curve (AUC) (968.78+/-259.39 microg min mL(-1) versus 509.84+/-46.19 microg min mL(-1) in normal rats P < 0.05). The system clearance (CL) and renal clearance (CL(R)) of antofloxacin decreased from 12.66+/-1.15 mL kg(-1) min(-1) and 3.21+/-1.80 mL kg(-1) min(-1) in normal rats, to 6.63+/-2.82 mL kg(-1) min(-1) and 0.31+/-0.15 mL kg(-1)min(-1), respectively. No differences between two treatments in half-life and mean residence time were found. We concluded that renal impairment induced by cisplatin significantly altered the pharma-cokinetics of antofloxacin and resulted in decrease of the renal elimination.     

An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole.

1. The oral pharmacokinetics of fluconazole were studied in three groups of volunteers (n = 5) with various degrees of renal function (GFR greater than 70 ml min-1; 20-70 ml min-1; less than 20 ml min-1) and in a group of patients with chronic end-stage renal failure requiring regular haemodialysis. 2. The pharmacokinetics of fluconazole were markedly affected by impaired renal function with the elimination of half-life in Group III (GFR less than 20 ml min-1) being approximately three times that observed in normal volunteers (Group I). 3. Fluconazole renal clearance was positively correlated with GFR. 4. Non-renal clearance of fluconazole decreased with decreasing renal function. 5. Approximately 38% of the 50 mg dose of fluconazole was removed by haemodialysis extending over a 3 h period.     

On the assessment of effects of food on the pharmacokinetics of drugs in early development

The impact of food on the pharmacokinetics of a drug has important implications in drug development. This commentary is aimed at addressing two key challenges, developability of drugs whose pharmacokinetics are severely influenced by food, and the need for addressing the effects of fruit juice ingredients which modulate metabolic/efflux properties of a compound. Perspectives on the value in predicting food-drug interactions during preclinical development, timing of clinical food-drug interaction studies, and implications of food effects are presented herein.     

Influence of exercise on the pharmacokinetics of drugs

Since many patients with a wide variety of diseases are nowadays stimulated to adopt a physically active lifestyle, the question of the influence of exercise on the pharmacokinetics of drugs has become more and more relevant. Because exercise influences a large number of physiological factors that also determine the pharmacokinetics of drugs, including haemodynamics, metabolism, pH, temperature and gastrointestinal function, it can be expected to have an effect on the pharmacokinetic parameters (absorption, distribution, elimination) of certain agents. However, only a very limited number of studies has been directed towards this issue, and only a very few drugs have been studied. Nevertheless, it is clear that exercise does influence the pharmacokinetics of certain drugs, although the magnitude and direction of the effects vary. This is not surprising in view of the widely differing physicochemical properties of drugs, the many possible--often opposing--effects of exercise on the parameters affecting drug pharmacokinetics and the different types of exercise performed. The chance of a clinically relevant effect of exercise on the pharmacokinetics of a particular drug is largest in those with a steep dose-response curve, a narrow therapeutic range, a need for continuity of therapeutic effectiveness and a relatively short half-life, in combination with intensive exercise of long duration. If untoward drug effects occur during or after exercise, a change in the pharmacokinetics of the drug related to the exercise should be seriously considered as a possible cause.     

Cellular pharmacokinetics: effects of cytoplasmic diffusion and binding on organ transit time distribution

Distribution between well-stirred compartments is the classical paradigm in pharmacokinetics. Also in capillary-issue exchange modeling a barrier-limited approach is mostly adopted. As a consequence of tissue binding, however, drug distribution cannot be regarded as instantaneous even at the cellular level and the distribution process consists of at least two components: transmembrane exchange and cytoplasmic transport. Two concepts have been proposed for the cytoplasmic distribution process of hydrophobic or amphipathic molecules, (i) slowing of diffusion due to instantaneous binding to immobile cellular structures and (ii) slow binding after instantaneous distribution throughout the cytosol. The purpose of this study was to develop a general approach for comparing both models using a stochastic model of intra- and extravascular drug distribution. Criteria for model discrimination are developed using the first three central moments (mean, variance, and skewness) of the cellular residence time and organ transit time distribution, respectively. After matching the models for the relative dispersion the remaining differences in relative skewness are predicted, discussing the relative roles of membrane permeability, cellular binding and cytoplasmic transport. It is shown under which conditions the models are indistinguishable on the basis of venous organ outflow concentration-time curves. The relative dispersion of cellular residence times is introduced as a model-independent measure of cytoplasmic equilibration kinetics, which indicates whether diffusion through the cytoplasm is rate limiting. If differences in outflow curve shapes (their relative skewness) cannot be detected, independent information on binding and/or diffusion kinetics is necessary to avoid model misspecification. The method is applied to previously published hepatic outflow data of enalaprilat, triiodothyronine, and diclofenac. It provides a general framework for the modeling of cellular pharmacokinetics.     

The pharmacokinetics of non-steroidal anti-inflammatory drugs in the elderly

The elderly often suffer from chronic musculoskeletal disease, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control symptoms. The aged have been shown to be particularly at risk of adverse effects from these drugs, of which gastrointestinal irritation and bleeding are both common and potentially serious. Because of this, a comparison of NSAID pharmacokinetics in young and elderly subjects is of particular importance. In general, protein binding tends to decrease with age; volumes of distribution may undergo a small increase; and clearance, especially of renally eliminated drugs, may fall. However, these changes are relatively minor, and the increased propensity of the elderly to suffer adverse reactions to NSAIDs cannot readily be explained on a pharmacokinetic basis.     

The pharmacokinetics of tricyclic antidepressant drugs in the elderly

Antidepressants, especially tricyclic agents (TCAs), are increasingly used in geriatric patients since depression is a common mood disorder in the elderly and the size of elderly population is increasing. Notwithstanding the importance of kinetics to better use of drugs, its study in the elderly (regarding TCAs) is not sufficiently developed. The present paper briefly reviews the available data on amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine kinetics in the elderly.     

生物技术药物药代动力学研究进展

生物技术药物作为现代药物研发热点而备受关注,它具有和传统小分子药物截然不同的理化性质,因此其药动学呈现出独特性和复杂性。阐述生物技术药物的概念;总结4种主要的生物技术药物分析方法;进一步综述生物技术药物在体内吸收、分布、代谢和排泄的药动学特点;最后以生物技术药物主流之一的单克隆抗体药物为代表,通过相关数据对比单克隆抗体药物与传统小分子药物在药动学方面的差异。以期为充分了解生物技术药物的药动学特征以及形成机制、研发和筛选新型生物技术药物提供强有力的支持,同时为药物安全性评价和临床用药提供重要参考。     

Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies.

It is well known that intake of grapefruit juice affects the pharmacokinetics of various kinds of drugs. It has been reported that other citrus juices also interact with certain drugs. To re-evaluate citrus juice-drug interactions based on currently available evidence, a literature search was conducted for new and updated information since the grapefruit juice-drug interaction was last reviewed in 1998. MEDLINE (1998-October 2004) was accessed and more than 200 reports were found. The effects of grapefruit juice ingestion on the pharmacokinetics of orally administered drugs have been reported for 40 drugs since the reviews published in 1998. Increases in either area under the concentration-time curve (AUC) or maximum plasma concentration (C(max)) were found with 34 of these, the major mechanism being considered to be inactivation of intestinal cytochrome P450 3A4, a so-called mechanism-based inhibition. Although recent reports point to the inhibitory effects of grapefruit juice on the function of P-glycoprotein, which transports substrates from enterocytes back into the lumen, the contribution to the bioavailability of drugs that are substrates of P-glycoprotein has not been established yet. Dramatic decreases in AUC and C(max) for two drugs in association with grapefruit juice ingestion has been reported and, in these cases, inhibitory effects on organic anion transporting polypeptide, which mediates absorption from the intestinal lumen to enterocytes, might be involved. Other citrus juices such as Seville (sour) orange juice and commonly ingested varieties of orange juice also showed significant effects on the AUC and C(max) of some drugs. Although the situation is complex and uncertainties remain, we recommend that patients avoid citrus juice intake while taking medications and that healthcare providers advise against citrus juice intake in this setting until any interactions with subject drugs can be clarified in clinical studies.     

The effects of lamotrigine on the pharmacokinetics of lithium

AIMS: The treatment of bipolar disorder often includes use of multiple drug therapies. Lithium is one of the most commonly used treatments, but has a narrow therapeutic window. Lamotrigine, an established antiepileptic drug, is emerging as a potentially important new therapy in the treatment of bipolar disorder. The objective of this two-treatment crossover study was to determine whether lamotrigine affects lithium pharmacokinetics. METHODS: Twenty healthy adult men completed the study. Subjects took 2 g lithium gluconate anhydrous every 12 h in the morning and evening for 5 days and in the morning of day 6, with or without 100 mg lamotrigine once daily in the morning for 6 days. Blood and urine samples were collected on day 6 of both treatments to characterize the pharmacokinetics of lithium using noncompartmental methods. RESULTS: The geometric least-square mean ratio for renal clearance of lithium between the combination treatment and lithium alone treatment was 0.93 (95% confidence interval 0.85-1.02). Both treatments were well tolerated. CONCLUSIONS: Lamotrigine does not cause significant change in the pharmacokinetics of lithium.     

Clinical pharmacokinetics of the antituberculosis drugs

The quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable 'first-pass' effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid. With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug's antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide. The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group.(ABSTRACT TRUNCATED AT 400 WORDS)     

The pharmacokinetics of pioglitazone in patients with impaired renal function

AIMS: To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. METHODS: In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). RESULTS: Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. CONCLUSIONS: Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.     

The pharmacokinetics of lamivudine in patients with impaired hepatic function

Objective: This study was designed to evaluate the effect of hepatic impairment on the pharmacokinetics of lamivudine. Methods: Sixteen patients not infected with hepatitis B virus or human immunodeficiency virus who had hepatic impairment due to liver cirrhosis were assigned to moderately or severely impaired groups by clinical signs/symptoms, ¹⁴C-aminopyrine metabolic activity and caffeine clearance and compared with eight healthy controls. Following a 300-mg dose of lamivudine, blood and urine samples were taken for drug assay. Results: Lamivudine was well tolerated in patients with hepatic impairment. There were no statistical differences in overall lamivudine exposure (in terms of AUC or C_max) or other major pharmacokinetic parameters i.e. CL_R, t_max and t_1/2, between healthy control subjects and patients with moderate or severe hepatic impairment. Conclusions: Hepatic impairment does not warrant dose modification of lamivudine based on this single-dose pharmacokinetic study. Received: 5 September 1997 / Accepted in revised form: 7 February 1998     

Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs

Since renal failure itself creates an immunocompromised situation, malignant tumours in haemodialysis patients are increasing due to the prolonged lifespan of these patients. In treating these patients with anticancer agents, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs with extensive renal excretion. On the other hand, if an anticancer drug is removed significantly by haemodialysis, dosage increase would be required to ensure adequate therapeutic efficacy. We address in this review the clinical pharmacokinetic aspects of antineoplastic therapy, and the application of pharmacokinetic principles to the adjustment of dosage of anticancer agents in haemodialysis patients.     

The effects of grapefruit juice on the pharmacokinetics of erythromycin

OBJECTIVE: To study the effects of grapefruit juice on the pharmacokinetics of erythromycin. METHODS: The effects of grapefruit juice intake on the pharmacokinetics of erythromycin were investigated in six healthy male volunteers, who received 400 mg erythromycin with either water or grapefruit juice. The measurement of erythromycin in plasma samples were achieved by simple Sep-Pak CN cartridge extraction coupled with the electrochemical determination HPLC method, which was developed for the determination of erythromycin in human plasma in the present study. RESULTS: Grapefruit juice, compared with water intake, significantly (P<0.05) increased the mean Cmax value (1.65+/-0.94 versus 2.51+/-0.68 microg/ml) and the mean AUC0-12 value of erythromycin (5.92+/-3.25 versus 8.80+/-1.32microg.h/ml). However, the Tmax and t1/2 values of erythromycin were not affected by grapefruit juice intake. CONCLUSION: These results indicate that the bioavailability of erythromycin was increased by the inhibitory effect of grapefruit juice on cytochrome P450 (CYP) 3A4-mediated metabolism in the small intestine.