Pharmacodynamics active metabolites

This hypothesis clearly contradicted a large body of clinical evidence that nitrates were effective. Some years later, using more sensitive and reliable analytical methods, this interpretation was shown to be incorrect, and the clinical utility of long-acting, oral organic nitrate derivatives affirmed. In 1967, one of the pharmacodynamically active metabolites of ISDN, IS-5N, was shown to be formed in vivo, and shortly thereafter it was introduced as a novel long-acting NO donor with improved bioavailability. 

Pharmacokinetic—pharmacodynamic characterization of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites.53... 

The presence of therapeutically active metabolites that may contribute to the pharmacodynamic and toxic effects. 

Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome. 

Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran a mini-review. Thromb Res 2003 109(suppl I ) S9-S I 5. 

This chapter reviews the bioanalytical developments by mass spectrometry in the field of targeted anticancer therapy, across the growing family of recent FDA-approved oral TKIs as well as tamoxifen and its active metabolites. The text also provides an introduction to existing pharmacokinetics-pharmacodynamics knowledge in the field of targeted anticancer therapy. 

The effects of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone have been investigated in 10 healthy volunteers. Fluvoxamine moderately increased plasma buspirone concentrations and reduced the production of the active metabolite of buspirone. The mechanism of this interaction is probably inhibition of CYP3A4. However, this pharmacokinetic interaction was not associated with impaired psychomotor performance and is probably of limited clinical significance (33). 

Tuk, B., Van Oostenhmggen, M.F., Herhen, V.M.M., Mandema, J.W., Danhof, M. (1999). Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo midazolam and alpha-OH-midazolam. J. Pharmacol. Exp. Then 289 1067-74. 

While it is often held that genetic polymorphisms are most important when they affect drugs that have a narrow therapeutic index for which dangerous toxicity may result or perilous lack of effect may ensue/ this need not be the case. For example/ CYP2D6 converts codeine/ likely the most widely prescribed opiate in the world and the mainstay of pain control for a large number of patientS/ to its active metabolite morphine. ThuS/ patients who have deficient CYP2D6 are unable to make morphine/ and pharmacodynamic studies have shown that this results in decreased pain... 

Administration of grapefruit juice (which inhibits both cytochrome P450 and P glycoprotein) to healthy volunteers resulted in an increased serum concentration ratio of losartan to its active metabolite E3174 (27). As both losartan and its metabolite contribute to the therapeutic effects, the absence of pharmacodynamic measurements in this study obviated conclusions about the clinical implications of this interaction. 

The clinical pharmacodynamics and pharmacokinetics of molindone (91) have been reviewed (525). The drug is reputed to be rapidly absorbed after oral administration and rapidly metabolized. Only 2-3% of the unchanged drug can be recovered in the urine and feces. Molindone has a very short half-like (1.5-2 h) and is 1.5-1.7 times more bioavailable after intramuscular, rather than oral, administration (526). Molindone is less lipophilic than most antipsychotic drugs and has a lower fraction (around 75%)that is bound to proteins in the plasma (527).Clinical studies indicate that the antipsychotic effectiveness of molindone lasts more than 24 h (525,528,5291, suggesting that one or more active metabolites may contribute to its actions in vivo. 

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the overall clearance of the drug, but may catalyze the formation of highly active metabolites. 

The blood or plasma concentrations of the parent drug and/or its active metabolites (systemic exposure) may provide an important link between drug dose (exposure) and desirable and/or undesirable drug effects (8). For this reason, the modeling of parent drug and metabolite pharmacokinetics, coupled with pharmacodynamic (PD) measurements, offers an essential development tool for prediction and simulation. 

Counterclockwise hysteresis loops can be caused by the accumulation of an active metabolite, sensitization to the drug, or delay in time in equilibration between serum concentration and concentration of drug at the site of action. Combined pharmacokinetic-pharmacodynamic models have been devised that allow equilibration lag times to be taken into account. 

Pharmacodynamics including, but not limited to, information on the mechanism of action favorable or unfavorable PD effect to plasma concentration of a drug candidate and/or active metabolite(s) (i.e., PK/PD relationships) PD support for proposed dose, dosing interval, and dosing duration possible genetic differences in PD response. 

As the compound reaches the late discovery and candidate selection stage, the focus is to determine its major metabolic pathways, metabolic difference between species, and to identify potential pharmacologically active or toxic metabolites. Because of the complexity, comprehensive metabolite characterization studies have been typically conducted at this stage with radiolabeled standard. Identification of circulating metabolites is also important at this stage to explain the pharmacokinetic or the pharmacodynamic profile. An NCE may show efficacy that is inconsistent with what is predicted based upon the known concentration of the parent drug. These inconsistencies could be due to the presence of active metabolites. The knowledge of these metabolites will also dictate how the analysis of samples will be conducted in the development and clinical studies. 

Two distinct bases for these types of effects may be distinguished pharmacokinetic and pharmacodynamic. Pharmacokinetic-based toxic effects are due to an increase in the concentration of the compound or active metabolite at the target site. This may be due to an increase in the dose, altered metabolism or saturation of elimination processes for example. An example is the increased hypotensive effect of debrisoquine in poor metabolizers where there is a genetic basis for a reduction in metabolic clearance of the drug (see Chapter 5). 

In spite of its rapid absorption and short half-life, the peak effect of methyldopa is delayed for 6 to 8 hours even after intravenons administration, and the duration of action of a single dose is nsnally about 24 hours this permits once-or twice-daily dosing. The discrepancy between the effects of methyldopa and the measured concentrations of the drug in plasma is most likely related to the time required for transport into the CNS, conversion to the active metabolite storage of a-methyl norepinephrine, and its subsequent release in the vicinity of relevant 0.2 receptors in the CNS. This is a good example of the potential for a complex relationship between a drug s pharmacokinetics and its pharmacodynamics. Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, bnt it is not known if this is due to alteration in excretion of the drng or to an increase in transport into the CNS. 

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