Pharmacokinetic effects

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

The following points are worthy of note in terms of the placement of data. In the case of studies with multiple objectives, reports should be placed in the section corresponding to their primary purpose. Reports of laboratory studies conducted with human materials to investigate pharmacokinetic effects should be placed in Section 5.3.2 of the clinical module, as opposed to the non-clinical module. A US submission requires that the individual case report forms of all trial subjects that died or were dropped from a study due to adverse events are included in Section 5.3.7. 

The same assumptions apply to CoMFA as to ordinary Hansch analysis. These are additivity of effects and the availability of structurally similar (congeneric) molecules. The method does not account for pharmacokinetic effects, such as distribution, elimination, transport and metabolization. A prospective drug may appear to bind well to the receptor or enzyme, but may not reach the target site due to undesirable pharmacokinetic properties [8]. 

In this example, clarithromycin, a potent CYP3A inhibitor blocks the principal pathway of pimozide metabolism (CYP3A), and plasma concentrations of pimozide increase. A higher pimozide concentration (a pharmacokinetic effect) is associated with prolongation of QT c in EKG readings and potentially fatal torsades de pointes (via potassium channel blockade, a pharmacodynamic effect see Flockhart et al., 2000, May-hew et ah, 2000). As exemplified by this vignette, the... 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

Accumulating data comparing response rates in men and women given either SRIs or TCAs show that women preferentially respond to SRIs. Although it is possible that this is a pharmacokinetic effect, one would argue that it is more likely to be a pharmacodynamic effect because plasma blood levels of SRIs are not linked to response. 

Hamilton JA, Grant M Sex differences in metabolism and pharmacokinetics Effects on agent choice and dosing. NIMH Conference, Bethesda, MD, November 4, 1993... 

Compared with chiroptical methods and nuclear magnetic resonance spectroscopy (NMR), only chiral chromatography by direct and indirect methods is suitable for the accurate determination of enantiomeric impurities of less than 1% and for quantitative stereochemical analyses of small sample amounts (for example, in vivo studies of the metabolic pathway or pharmacokinetic effects of chiral pharmaceuticals.)... 

Garnett WR, Venitz J, Wilkens RC, Dimenna G. Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin. Am J Med 1994 96(6A) S84-6. 

The next stage of assessment is multidose tolerance (MDT) study. The objective of this study is to assess pharmacodynamic and pharmacokinetic effects and to collect data for any adverse event observed. For this assessment, a range of doses is administered with placebocontrol to healthy volunteers for 7-14 days. The intention of these studies is to assess any potential saturation of metabolism. 

Estimates of responses at low doses derived from data on laboratory animals and extrapolated to humans are complicated by a variety of factors that differ among species and potentially affect the response to hazardous chemicals. These factors include differences between humans and experimental test animals with respect to life span, body size, genetic variability, population homogeneity, existence of concurrent disease, such pharmacokinetic effects as metabolism and excretion patterns, and the dosing regimen. These factors are discussed further in Section 3.2.1.5. 

Amikacin In vivo—sheep pharmacokinetics, effect of lipid composition [85]... 

Tobramycin In vivo—rats In vivo—rats In vitro In vivo—mice In vivo—rats Pharmacokinetics Pharmacokinetics, eradication of P. aeruginosa Drug release, effect of lipid composition Pharmacokinetics, effect of lipid composition Pharmacokinetics, eradication of P. aeruginosa [88] [87] [90] [89]... 

Amphotericin B In vivo—mice In vivo—mice In vivo—mice Treatment of pulmonary and systemic Cryptococcus neoformans infections Prophylaxis of pulmonary aspergillosis Pharmacokinetics, effect of lipid composition [91] [92] [93]... 

The drug is administered to a small group of healthy volunteers with the objective of determining the processes of absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic effects. Escalating doses are compared to choose one suitable for both safety and efficacy. 

IPCS Environmental Health Criteria Documents reflect the collective view of an international group of experts and do not necessarily represent the decision or stated policy of UNEP, ILO, or WHO. The reports summarize and interpret the pertinent published literature. Unpublished information is used when published information is absent or when data are pivotal to the risk assessment. Adequate human data are preferred to animal data. Topics include physical chemistry sources of exposure environmental fate and transport concentrations in the environment and in humans pharmacokinetics effects from acute, subacute, and long-term exposure toxic effects on skin, eye, and reproduction mutagenesis and cancer. 

OPIOIDS ANTIFUNGALS 1, Ketoconazole T effect of buprenorphine 2. Fluconazole and itraconazole T the effect of alfentanil 3. Fluconazole and possibly voriconazole T effect of methadone this is a recognized pharmacokinetic effect but of uncertain clinical significance 1. Ketoconazole 1 the CYP3A4-mediated metabolism of buprenorphine 2.1 clearance of alfentanil 3.1 hepatic metabolism 1. The dose of buprenorphine needs to be 1 (by up to 50%) 2. i dose of alfentanil 3. Watch for T effects of methadone... 

The inherent pharmacologic properties of a drug determine its pharmacodynamic effects, and drug absorption, distribution, metabolism, and excretion are determined by the pharmacokinetic effects. The ease with which a drug passes into the systemic circulation and its ability to penetrate the blood-brain, blood-aqueous, or blood-retinal barriers determines the propensity to affect ocular tissues and functions. 

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