Pharmacokinetics therapeutic activity

Pharmacokinetics is the study of how the body affects an adiriinistered dmg. It measures the kinetic relationships between the absorption, distribution, metaboHsm, and excretion of a dmg. To be a safe and effective dmg product, the dmg must reach the desired site of therapeutic activity and exist there for the desired time period in the concentration needed to achieve the desired effect. Too Htde of the dmg at such sites yields no positive effect ( MTC) leads to toxicity (see Fig. 1). For intravenous adininistration there is no absorption factor. Total body elimination includes both metabohc processing and excretion. 

Another type of therapeutically active molecule is one designed primarily with pharmacokinetics in mind (designed to be well absorbed and to enter the central compartment readily), which can then be converted to the therapeutically active molecule in the body. These are referred to as pro-drugs. This process, called latentiation, consists of the conversion of hydrophilic drugs into lipid-soluble drugs (usually by masking hydroxyl, carboxyl, and... 

Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004 1663(1-2) 167. 

In addition to toxicity and safety data, the preclini-cal package to start clinical studies also contains information on the pharmacology, the pharmacokinetics and metabolism and the galenical aspects of the compound. As a rule there is evidence of pharmacological activity and, if possible, of therapeutic activity in one or more animal models of disease. Ideally there is also information on the in vivo concentration effect relationship. 

All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. 

In the purposeful search that followed the demonstration of the clinical efficacy of penicillin, streptomycin was obtained from Streptomyces griseus in 1944, cultured from a heavily manured field, and also from a chicken s throat. Aminoglycosides resemble each other in their mode of action, and their pharmacokinetic, therapeutic and toxic properties. The main differences in usage reflect variation in their range of antibacterial activity crossresistance is variable. 

A relationship between pharmacokinetic data and pharmacodynamic activity is assumed. There is no interest in predicting variations in plasma concentration using a correlation if these have no measurable influence on pharmacodynamic and pharmacological activity, and therefore none on therapeutic effectiveness. In addition the moiety responsible of the therapeutic activity must be known. 

Calvert H, Judson I, van der Vijgh WJ. Platinum complexes in cancer medicine Pharmacokinetics and pharmacodynamics in relation to toxicity and therapeutic activity. Cancer Surv 1993 17 189-217. 

Important pharmacokinetic differences exist between the two drugs. Dacarbazine is poorly absorbed, and must be administered by intravenous infusion. Temozolomide is rapidly absorbed after oral administration, and is approximately 100% bioavailable when given on a completely empty stomach. Darcarbazine penetrates the CNS poorly, but temozolomide readily crosses the blood-brain barrier, achieving therapeutically active concentrations in cerebrospinal fluid and brain tumor tissues. ... 

In contrast to metabolic stabilization, metabolic switching is a versatile means of deflecting metabolism away from toxic products to enhance the formation of therapeutically active metabolites and/or to obtain a suitable pharmacokinetic behavior. 

Paliperidone, or 9-hydroxyrisperidone, is the major active metabolite of risperidone. It binds to both dopamine Dj and serotonin 5-HT2A receptors, and antagonism at these receptors is thought to account for its therapeutic activity in schizophrenia. It was approved by the US Food and Drug Administration in 2007 for acute and maintenance treatment of schizophrenia it is available in modified-release tablets. The available literature on the pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability of paliperidone has been extensively reviewed [101 ]. 

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