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The contribution of Drug metabolites to drug-drug

interactionPresented ByRavi Goyani

M.S(Pharm.)Pharmaceutics I.D.No.307/14IInd semester

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Contents1. Introduction2. Drug-drug interaction3. Regulatory perspectives of drug-drug interaction4. Potential pharmacokinetic interaction produced by

metabolites 5. Case study6. Evaluation of metabolites to drug interaction7. Conclusion 8. References

IntroductionA metabolites is any chemical compound produced as a

result of metabolism or a metabolic reaction.When patient are administered a medication, they are

exposed to not only the parent drug itself, but also drug metabolites which is generated in situ as natural process of drug metabolism.

Examples of metaolites Morphine Codeine Phenobarbital Primidone Enalaprilat Enalapril Desipramine Imipramine

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Types of metabolitesInactive metabolitesMetabolite retaining similar activityMetabolites with different activityBioactive metabolites

Metabolites formed by the phase I and phase II metabolism

process, in which lipophilic molecules converted to the hydrophilic drugs and Conjugation of metabolites for readily excreted in to the urine respectively.

Formation of metabolites

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Drug-drug interactionPharmacodynamic drug-drug interaction Antagonism means that one drug reduces or

blocks the effect of another. There are various ways in which this can happen. For instance, drugs can interfere with each other's absorption in the gut, circulation in the blood, or uptake by cells.

Synergism means that two or more drugs work together against one target, producing an effect that is greater than the individual effect of the two drugs together.

Potentiation means that drug A boosts the effects of drug B, often by increasing the levels of drug B in the blood. Like synergism, this may be useful in cases in which the beneficial effects of drug B are enhanced.

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Potential pharmacokinetic interactionPharmacokinetic interactions occur when the absorption,

distribution, metabolism or elimination processes of the object drug is altered by the precipitant drug.

drug metabolites is the potential for the cause pharmacokinetics drug interaction that would not caused by the parent drug itself.

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Pharmacokinetics drug interaction

Enzymes inducer Enzymes inhibitor Some drugs are converted to

toxic metabolites by enzymes and enzyme inducers can increase the formation of these toxic metabolites.

Paracetamol is primarily converted to nontoxic metabolites but a small amount is converted to toxic metabolites; however if administered with an enzyme inducer it could lead to hepato-toxicity.

Clinically relevant interactions of inhibited drug metabolism occurring through oxidative processes include inhibition of warfarin metabolism by phenylbutazone, cimetidine, chloramphenicol, and metronidazole.

Inhibition of theophylline metabolism by quinolones and macrolides and inhibition of phenytoin by isoniazid resulting in increased therapeutic levels and toxicity.

Regulatory perspective on drug-drug interactionEuropean Medicines Agency(EMA) guideline on the

investigation of drug interaction and the draft guidances on the drug interaction studies from the the FDA have proposed that metabolites which are present at > 25% of the parent area under the concentration /time curves (AUC) and >10 % of total drug related exposure should trigger further in vitro characterization of the metabolites a possible contributor to DDIs arising from cyp450 inhibition.

Guidance from the Food and Drug Administration on drug interaction studies does not include a specific section on contributions of metabolites to observed inhibitory drug-drug interactions, and the quantitative role of drug metabolites in inhibitory drug-drug interactions is not presently known.

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The International Conference on Harmonisation M3 guideline recently issued by the European Medicines Agency, on the other hand, focuses on metabolites that circulate at 10% of total drug-related material.

The presence or absence of a drug interaction in clinical studies is determined by statistical analysis. If the 90% confidence interval for the ratio of pharmacokinetic parameters (Cmax and AUC) falls between 0.80-1.25, a pharmacokinetic drug interaction is generally considered negative. It is necessary, however, to remember that drug interactions within this range may cause clinically significant adverse effects

Criteria for the absence of a based drug interaction on the results of a clinical study

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Case study

Efavirenz is metabolized mainly by CYP2B6 to two metabolites: 8-hydroxyefavirenz (major) and 8,14-dihydroxyefavirenz (minor),and is an example of a drug that has a circulating metabolite that appears to be responsible for protein adduct formation.

Efavirenz and both metabolites contain an ethynyl group, which is a known alert for P450 mechanism-based inactivation, particularly with the CYP2B family of enzymes.

Both efavirenz and its major metabolite 8-hydroxyefavirenz inhibit the inactivation by efavirenz.

Irreversible inhibition by P450 protein adduct

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The metabolism of efavirenz and 8-hydroxylefavirenz CYP2B6 but the inactivation of CYP2B6 by 8- hydroxyefavirenz was markedly different from by CYP2B6 leads to inhibition by two distinct mechanisms although the reactive species responsible for the inactivation are not yet known.

Efavirenz was a potent apparent reversible inhibitor (time and concentration-dependent inactivation, whereas the 8-hydroxylefavirenz was an irreversible inhibitor.

Based on this in vitro data, it appears that for in vitro to in vivo extrapolation of CYP2B6 inactivation after efavirenz administration, 8-hydroxyefavirenz rather than efavirenz should be modeled.

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Verapamil has two major metabolites formed by CYP3A4 via N-dealkylation: N-desalkylverapamil (D-617) and norverapamil. Verapamil and these two major metabolites form MI complexes with CYP3A4.

Based on the ratio of Kinact to Ki, the inactivation potency was norverapamil> verapamil > D-617. Although the plasma concentration of D-617 is comparable to verapamil and norverapamil, and D-617 is a secondary amine, the potency of inactivation is weak and D-617 probably does not contribute to the in vivo inactivation.

However, the steady-state levels of norverapamil reach that of verapamil and incorporating the inactivation kinetics of the secondary amine metabolite improved the in vivo predictions

Irreversible inhibition of P450 by metabolites intermediate complex formation

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Evaluation of metaolites drug interaction

1. Estimation of metabolites concentration

2. Metabolites and parent cytochrome P450 inhibition potency comparison

3. RMet strategy

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Estimation of metabolites concentrationMetabolites concentration were estimated by

multiplying the metabolites/parent ratio from the human ADME study by maximal plasma concentration in micromolars of the parent following multiple dosing in the phase 2 or 3 clinical studies.

For this study investigator brochure were used as source documents for parent M.W relevant clinical doses and steady state Cmax in the clinical studies.

Estimated metabolites concentration were categorized as <1, 1-10,>10 µM.

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Metabolites and cytochrome P450 inhibition potency comparison

The measured in vitro cytochrome P450 Ki values of metabolites and respective parent compounds were compared .

Based on relative potency between the matabolites and parents, compounds were placed in the following categories.

1. Metabolites <1x more potent than parent2. Metabolites 1-4x more potent than parent3. Metabolites >4x more potent than parentFor each metabolites/parent pair ,fold differences in Ki,

metabolic modification and relevant cytochrome P450s were reported.

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RMet strategy RMet is defined as the circulating metabolites

concentration(Imet) divided by the in vitro metabolites(Kimet) values for inhibition of cytochrome P450 isozymes.

Measured metabolites Cmax and Ki were used in RMet anlaysis from prepared metabolites standard.

In other cases metabolites concentration were estimated using high pressure liquid chromatography-radiometric analysis of human plasma samples from the human radiolabel study.

The Rmet analysis can play an important role in ruling out compounds for potential matabolites mediated DDIs,a systemic approach is needed to identify which metabolites may contributes to cause metabolites mediated DDIs.

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Figure 1. Proposed algorithm for the evaluation of drug metabolites interaction.

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Conclusion Drug interaction of drug metabolites mainly depend

on to the formation of metabolites in to the phase 1/II metabolism process in which activity of metabolites than parent drugs either induce or inhibit the metabolic process. Induction and inhibition of the CYP 450 is main causes of drug interaction. Regulatory perspective of the study of drug interaction involved in vivo an in vitro study data. Evaluation of drug interaction causes by metabolite mainly focuses on to the determination of parent/metabolites concentration in vivo as well as in vitro study of drug. It can be concluded that metabolite produced by metabolism that may be toxic/inactive/bioactive influenced in to the drug-drug interaction.

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References1. Callegari E, Kalgutkar AS, Leung L, Obach RS. Drug Metabolites as

Cytochrome P450 Inhibitors: A retrospective analysis and proposed algorithm for evaluation of the pharmacokinetic interaction potential of metabolites in drug discovery and development. Drug Metabolism and Disposition. 2013;41:2047–2055.

2. Hongbin Y, Tweedie D. A perspective on contribution of metabolites to drug drug interaction potential The need to consider both circulating levels and inhibition potency Drug Metabolism Disposition. 2013;41:536–540.

3. Brooke M, Vanden B, Isoherranen N. The role of metabolites in predicting drug-drug interactions: Focus on irreversible P450 inhibition. Current Opinion Drug Discovery and Development. 2010;13(1): 66–77.

4. Guideline on the investigation of drug interactions. European Medicine Agency.2012:1-60.

5. Isoherranen N, Hachad H, Yeung C, Levy R. Qualitative analysis of the role of metabolites in inhibitory Drug-drug interactions: literature evaluation based on the metabolism and transport Drug interaction database. Chemical Research Toxicology. 2009;22(2):294–298.

6. Yeung CK, Fujioka Y, Hachad H, Lev RH, Isoherranen N. Are Circulating Metabolites Important in Drug–Drug Interactions?: Quantitative analysis of risk prediction and inhibitory potency. Clinical Pharmacology & Therapeutics. 2011;89(1):105-112.

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