Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach, R. Scott

doi:10.1124/pr.111.005439

Cited by 137 publications

(103 citation statements)

References 329 publications

(280 reference statements)

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“…[1,2] Many successful examples have been reviewed in the literature. [1][2][3] A detailed discussion of prodrugs and their active metabolites (parent drugs) is beyond the scope of this tutorial. Here we focus on the pharmacokinetics of a prodrug and its metabolite to help understand their pharmacokinetic data obtained from preclinical and clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Understanding the pharmacokinetics of prodrug and metabolite

Cho

Yoon

2018

Transl Clin Pharmacol

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This tutorial explains the pharmacokinetics of a prodrug and its active metabolite (or parent drug) using a two-step, consecutive, first-order irreversible reaction as a basic model for prodrug metabolism. In this model, the prodrug is metabolized and produces the parent drug, which is subsequently eliminated. The mathematical expressions for pharmacokinetic parameters were derived step by step. In addition, we visualized these expressions to help understand the relationship between pharmacokinetic parameters easily. For the elimination rate-limited and formation rate-limited metabolism, we analyzed the plasma drug concentration versus time curve of a prodrug administered intravenously. IntroductionProdrug is a pharmacologically inactive derivative of an active drug and undergoes in vivo biotransformation to release the active drug by chemical or enzymatic cleavages.[1-3] A prodrug strategy is typically used when a pharmacologically active drug has poor solubility or permeability.[1,2] Various chemically or enzymatically labile functional groups have been introduced to improve the properties of the parent drug and decrease the presystemic metabolism.[1,2] Many successful examples have been reviewed in the literature.[1-3] A detailed discussion of prodrugs and their active metabolites (parent drugs) is beyond the scope of this tutorial. Here we focus on the pharmacokinetics of a prodrug and its metabolite to help understand their pharmacokinetic data obtained from preclinical and clinical studies. This will ultimately help define the proper dose of the prodrug needed for efficacy. Theoretical Analysis Prodrug KineticsWhen a prodrug is administered orally, it undergoes complicate processes of absorption, distribution, metabolism, and excretion. To understand these processes for metabolites, Cummings and Martin published results on the excretion and accrual of drug metabolites in 1963. [4] This provides the basis for the pharmacokinetics of drug and its metabolites and can be readily applied to study the pharmacokinetics of prodrug. Since then, many theoretical analyses and reviews, related to prodrug pharmacokinetics, have been published.[5-10] A thorough understanding of prodrug kinetics is daunting and may be achieved using sophisticated physiologically based pharmacokinetic (PBPK) modeling. [11,12] To get some insight pertinent to prodrug kinetics, we consider a simple scheme for the fate of a prodrug (P) after intravenous administration (Fig. 1). A fraction of the prodrug (f) is metabolized and produces a parent drug (D) with a first-order formation rate constant, k f(D) . The drug (D) may be further metabolized to a daughter metabolite (DM 1 ) or excreted. The elimination rate constant of the parent drug, k el(D) , is expressed by the sum of the formation rate constant of the daughter metabolite, k f(DM1) , and the urinary excretion rate constant, k ex(D) . More than one metabolite may be formed with a formation rate constant, k f(PM2) , and then excreted with a rate constant, k ex(PM2) . Otherwise, a fractio...

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Section: Introductionmentioning

confidence: 99%

“…[1][2][3] A prodrug strategy is typically used when a pharmacologically active drug has poor solubility or permeability. [1,2] Various chemically or enzymatically labile functional groups have been introduced to improve the properties of the parent drug and decrease the presystemic metabolism.…”

Section: Introductionmentioning

confidence: 99%

Understanding the pharmacokinetics of prodrug and metabolite

Cho

Yoon

2018

Transl Clin Pharmacol

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“…By plotting the PDE2 activity observed in each well against the time of collection for each well, a chromatographic representation of pharmacologic activity was made. This representation has been called an activity-gram, (Obach, 2013). This activity-gram showed that the two hydroxyl metabolites could have PDE2 inhibition activity, albeit the signal was weak.…”

Section: General Methodsmentioning

confidence: 99%

“…Knowledge of enzymes responsible for clearance can permit an understanding of the potential for interpatient variability in pharmacokinetics, drug-drug interactions, and the impact of genetic polymorphisms on drug and metabolite exposure (Zhang et al, 2007). Second, drug metabolites can possess similar binding potency to the same pharmacologic target as the parent drug, and thus could contribute to the clinical effect (Obach, 2013). Knowledge of potency, pharmacokinetics, and target tissue distribution of active metabolites is important for establishing the pharmacokinetic-pharmacodynamic relationship and dosing regimen.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Drug Metabolites and Quantitation Using NMR Spectroscopy for Use in Pharmacologic and Drug Metabolism Studies

et al. 2014

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The contribution of drug metabolites to the pharmacologic and toxicologic activity of a drug can be important; however, for a variety of reasons metabolites can frequently be difficult to synthesize. To meet the need of having samples of drug metabolites for further study, we have developed biosynthetic methods coupled with quantitative NMR spectroscopy (qNMR) to generate solutions of metabolites of known structure and concentration. These quantitative samples can be used in a variety of ways when a synthetic sample is unavailable, including pharmacologic assays, standards for in vitro work to help establish clearance pathways, and/or as analytical standards for bioanalytical work to ascertain exposure, among others. We illustrate five examples of metabolite biosynthesis and qNMR. The types of metabolites include one glucuronide and four oxidative products. Concentrations of the isolated metabolite stock solutions ranged from 0.048 to 8.3 mM, with volumes from approximately 0.04 to 0.150 ml in hexadeutarated dimethylsulfoxide. These specific quantified isolates were used as standards in the drug discovery setting as substrates in pharmacology assays, for bioanalytical assays to establish exposure, and in variety of routine absorption, distribution, metabolism, and excretion assays, such as protein binding and determining blood-toplasma ratios. The methods used to generate these materials are described in detail with the objective that these methods can be generally used for metabolite biosynthesis and isolation.

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“…To this end, we have developed a method whereby human plasma samples from subjects dosed with the drug candidate can be used to test for inhibition of P450, thereby obviating the need for identification, synthesis, testing, and measurement of plasma concentrations of metabolites. This approach (termed "activity-grams") was previously used to find pharmacologically active metabolites (Obach, 2013;Sawant-Basak et al, 2013;Walker et al, 2014). It has now been applied for P450 inhibition using control human plasma to which relevant concentrations of drug and metabolite(s) for seven drugs were added.…”

Section: Introductionmentioning

confidence: 99%

Use of Human Plasma Samples to Identify Circulating Drug Metabolites that Inhibit Cytochrome P450 Enzymes

Eng

Obach

2016

Drug Metabolism and Disposition

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Drug interactions elicited through inhibition of cytochrome P450 (P450) enzymes are important in pharmacotherapy. Recently, greater attention has been focused on not only parent drugs inhibiting P450 enzymes but also on possible inhibition of these enzymes by circulating metabolites. In this report, an ex vivo method whereby the potential for circulating metabolites to be inhibitors of P450 enzymes is described. To test this method, seven drugs and their known plasma metabolites were added to control human plasma at concentrations previously reported to occur in humans after administration of the parent drug. A volume of plasma for each drug based on the known inhibitory potency and time-averaged concentration of the parent drug was extracted and fractionated by high-pressure liquid chromatography-mass spectrometry, and the fractions were tested for inhibition of six human P450 enzyme activities (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Observation of inhibition in fractions that correspond to the retention times of metabolites indicates that the metabolite has the potential to contribute to P450 inhibition in vivo. Using this approach, norfluoxetine, hydroxyitraconazole, desmethyldiltiazem, desacetyldiltiazem, desethylamiodarone, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion were identified as circulating metabolites that inhibit P450 activities at a similar or greater extent as the parent drug. A decision tree is presented outlining how this method can be used to determine when a deeper investigation of the P450 inhibition properties of a drug metabolite is warranted.

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Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Cited by 137 publications

References 329 publications

Understanding the pharmacokinetics of prodrug and metabolite

Understanding the pharmacokinetics of prodrug and metabolite

Biosynthesis of Drug Metabolites and Quantitation Using NMR Spectroscopy for Use in Pharmacologic and Drug Metabolism Studies

Use of Human Plasma Samples to Identify Circulating Drug Metabolites that Inhibit Cytochrome P450 Enzymes

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