Hartmut Derendorf

Pharmacokinetics and bioavailability of quercetin glycosides in humans

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four‐way crossover study. Each subject received an onion supplement or quercetin‐4′‐O‐glucoside (both equivalent to 100 mg quercetin), as well as quercetin‐3‐O‐rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12‐channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin‐4′‐O‐glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL−1 and 2.1 ± 1.6 μg•mL−1 (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL−1 and 0.3 ± 0.3 μg•mL−1, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half‐life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin‐4′‐O‐glucoside and quercetin‐3‐O‐rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b‐glucosidases, needs to be further evaluated.

How Important Are Gender Differences in Pharmacokinetics

Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors.Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men.Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men.Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, β-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.

Pharmacokinetic/Pharmacodynamic Profile of Posaconazole

Posaconazole is a recently approved lipophilic triazole antifungal agent that exhibits potent and broad-spectrum antifungal activity in vitro and in vivo against most Candida spp., Cryptococcus neoformans, Aspergillus spp., many Zygomycetes, endemic fungi and dermatophytes. It has been documented that posaconazole has potency and spectrum of activity similar to those of itraconazole and superior to those of fluconazole against clinically important isolates of Candida spp., C. neoformans and Aspergillus spp. This new triazole has been developed for the treatment of fungal infections, which most often occur in severely immunocompromised patients, such as organ transplant patients or cancer patients undergoing chemotherapy. Since posanconazole has low solubility in aqueous and acidic media, its absorption is dose limited and significantly dependent upon food intake. The time to reach the maximum plasma concentration has been reported to be 5–8 hours following oral administration of a single dose. The relative bioavailability of posaconazole has been estimated to be significantly different among regimens and has been observed to be significantly increased by administration in divided doses. Posaconazole binds predominantly to albumin, and the extent of protein binding is high (>98%). Posaconazole has a large mean apparent volume of distribution after oral administration (Vd/F), which is approximately 5–25 L/kg, suggesting extensive extravascular distribution and penetration into intracellular spaces. The Vd/F is influenced by the dosage regimen. Since food significantly increases its bioavailability, posaconazole should be administered with a full meal whenever possible, to ensure optimal absorption. Posaconazole primarily circulates in plasma and then is widely distributed to the tissues and is slowly eliminated. Posaconazole is not metabolized to a significant extent through the cytochrome P450 (CYP) enzyme system and also has no effect on the CYP isoenzymes of 1A2, 2C8, 2C9, 2D6 and 2E1. The limited metabolism of posaconazole is mediated predominantly through phase 2 biotransformations via uridine diphosphate glucuronosyltransferase enzyme pathways. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Since posaconazole is an inhibitor primarily of CYP3A4, plasma concentrations of drugs that are predominantly metabolized by CYP3A4 may be increased by posaconazole. Posaconazole has a median terminal elimination half-life of 15–35 hours. The renal elimination of posaconazole is less than 1 mL/h, which is negligible compared with the mean total oral clearance of 16.3 L/h.Posaconazole shows potent in vitro activity against yeasts such as Candida spp. and C. neoformans, and against a range of moulds such as Aspergillus spp., as well as many dimorphic fungi and dermatophytes. Posaconazole has been shown to improve survival and/or to reduce the fungal tissue burden in animals infected with Blastomyces dermatitidis, C. neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Coccidioides immitis or Pseudallescheria boydii. The predictive pharmacokinetic/pharmacodynamic parameter for posaconazole treatment efficacy — the ratio between the mean free-drug area under the plasma concentration-time curve from 0 to 24 hours and the minimum inhibitory concentration (AUC24/MIC) — is about 17, which is similar to the value observed for other azoles in this infection model of disseminated Candida albicans infection.

AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development.

Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives

Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.

Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications.

Age-related changes in pharmacokinetics principally affect drug absorption, distribution, metabolism and elimination. Changes in pharmacodynamics are primarily seen in the cardiovascular and neuroendocrine system. Age-dependent changes in the kinetics and dynamics of drugs acting on the cardiovascular system and central nervous system are common, and this review, while by no means exhaustive of the effects of drugs on all organ systems, is reflective of the principles and gives examples of the effects of age on these 2 major systems. While pharmacokinetic changes in the elderly are usually well characterised, pharmacodynamic changes are understood only in the most preliminary way. There has been relatively little research in this area of geriatric clinical pharmacology, and pharmacodynamic changes are still an area of investigation.

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC

The success of antimicrobial therapy is determined by complex interactions between an administered drug, a host, and an infecting agent. In a clinical situation, the complexity of these interactions is usually reflected by a high variability in the dose-response relationship. Therefore, to minimize the dose-response variability, key characteristics of the drug, the infecting agent and the host have to be taken into account for selecting an appropriate antibiotic and an appropriate dose. Failure to do so may result in either therapeutic failure or emergence of resistant strains. To date, dose and drug selection is mostly based on a static in vitro parameter, the MIC and on the drug′s serum concentration as a pharmacokinetic parameter. In practice, however, a pharmacodynamic effect in vivo is rather the result of a dynamic exposure of the infective agent to the unbound antibiotic drug fraction at the relevant effect site. Thus, static conditions in an in vitro setting hardly reflect a dynamic situation in a target organ under in vivo conditions. Furthermore, serum concentrations do not reflect the unbound concentrations at the target site. In recent years substantial efforts were devoted to systematically elucidate the dynamic relationship between pharmacokinetic and pharmacodynamic variables. The main concept of this pharmacokinetic-pharmacodynamic approach is to use the concentration-effect relationship of the drug of interest in dosage adjustment and product development in a logical way and minimize trial-and-error approaches (29, 80). This approach can potentially result in substantial savings of time and expenses and may help to avoid unnecessary and, hence, unethical clinical studies (97). Thus, dosages and dosing intervals of antimicrobial agents should be designed with reference to dynamic pharmacokinetic and pharmacodynamic parameters. Accordingly, several efficacy indices or surrogate markers that take into account both pharmacokinetic and pharmacodynamic information have been defined and used by different authors to describe the antibacterial activity of various classes of antimicrobial agents (100, 106, 59). Currently there are two main trends for antibiotic pharmacokinetic-pharmacodynamic models; those based on the MIC and those based on a kill-curve approach, both of which will be described in detail in the following.

Pharmacokinetics and Bioavailability of Herbal Medicinal Products

The use of herbs for treating various ailments dates back several centuries. Usually, herbal medicine has relied on tradition that may or may not be supported by empirical data. The belief that natural medicines are much safer than synthetic drugs has gained popularity in recent years and led to tremendous growth of phytopharmaceutical usage. Market driven information on natural products is widespread and has further fostered their use in daily life. In most countries there is no universal regulatory system that insures the safety and activity of phytopharmaceuticals. Evidence-based verification of the efficacy of HMPs (herbal medicinal products, botanicals) is still frequently lacking. However, in recent years, data on evaluation of the therapeutic and toxic activity of herbal medicinal products became available. The advances in analytical technology have led to discovery of many new active constituents and an ever-increasing list of putatively active constituents. Establishing the pharmacological basis for efficacy of HMPs is a constant challenge. Of particular interest is the question of bioavailability to assess to what degree and how fast compounds are absorbed after administration of HMPs. Of further interest is the elucidation of metabolic pathways (yielding potentially new active compounds), and the assessment of elimination routes and their kinetics. These data become an important issue to link data from pharmacological assays and clinical effects. Of interest are currently also interactions of herbal medicinal products with synthetically derived drug products. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimens. In this review, pharmacokinetic and bioavailability studies that have been conducted for some of the more important or widely used phytopharmaceuticals are critically evaluated. Furthermore, various drug interactions are discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived active pharmaceutical ingredients.

Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra‐articular administration

Triamcinolone acetonide, triamcinolone hexacetonide, and a combination of betamethasone phosphate and acetate were given intra‐articularly in different doses. Plasma levels of the steroids were measured and pharmacokinetic parameters were calculated. As a pharmacodynamic parameter for systemic steroid activity, plasma hydrocortisone levels were monitored for 3 weeks. Results indicate complete absorption from the site of injection over a period of 2 to 3 weeks. Because of its lower solubility, triamcinolone hexacetonide is absorbed slower than triamcinolone acetonide, thus maintaining synovial levels for a longer time and creating lower systemic corticoid levels. Endogenous hydrocortisone suppression correlated with exogenous steroid levels. Threshold concentrations for maximum suppression were determined.

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids

There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process.