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  <front>
    <journal-meta>
      <journal-id journal-id-type="iso-abbrev">Pharmacophore</journal-id>
      <journal-id journal-id-type="publisher-id">pharmacophorejournal.com</journal-id>
      <journal-id journal-id-type="publisher-id">Pharmacophore</journal-id>
      <journal-title-group>
        <journal-title>Pharmacophore</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2229-5402</issn>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">pharmacophorejournal.com-6968</article-id>
      <article-id pub-id-type="doi">10.51847/XhzZht5y4r</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>A Causal Grammar for Drug–Drug Interactions from Molecular Initiation to Exposure Change and Clinical Consequence</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Joshi</surname>
                <given-names>Meenal</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Patil</surname>
                <given-names>Rohan</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Nair</surname>
                <given-names>Arjun</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Reddy</surname>
                <given-names>Pooja</given-names>
              </name>
                              <xref rid="aff4" ref-type="aff">4</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Causal Drug–Drug Interaction Modeling, Faculty of Pharmacy, Indian Institute of Science, Bengaluru, India.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Molecular Initiation and Exposure Change, Faculty of Pharmacy, IIT Bombay, Mumbai, India.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Clinical Consequence and Interaction Grammar, Faculty of Pharmaceutical Sciences, University of Delhi, Delhi, India.
          </aff>
                  <aff id="aff4">
            <label>4</label>Department of Pharmacological Causal Reasoning, Faculty of Pharmacy, University of Agricultural Sciences Dharwad, Dharwad, India.
          </aff>
                          <author-notes>
            <corresp id="cor1">
              <bold>Address for correspondence:</bold> Prof. Wael Abu Dayyih, Department of
              Pharmaceutical Chemistry, Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan.
                              E-mail: <email xlink:href="meenal.joshi@iisc.ac.in">meenal.joshi@iisc.ac.in</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>04</month>
        <year>2025</year>
      </pub-date>
      <volume>16</volume>
      <issue>2</issue>
      <fpage>86</fpage>
      <lpage>97</lpage>
      <permissions>
        <copyright-statement>
          Copyright: &#x000a9; 2026 Pharmacophore
        </copyright-statement>
        <copyright-year>2026</copyright-year>
        <license>
          <ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/"
            specific-use="textmining" content-type="ccbyncsalicense">
            https://creativecommons.org/licenses/by-nc-sa/4.0/</ali:license_ref>
          <license-p>This is an open access journal, and articles are distributed under the terms of
            the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
            others to remix, tweak, and build upon the work non-commercially, as long as appropriate
            credit is given and the new creations are licensed under the identical terms.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>A<sc>BSTRACT</sc></title>
        <p>Drug–drug interaction knowledge is distributed across molecular assays, enzyme and transporter studies, pharmacokinetic models, clinical investigations, computational predictions, knowledge bases, and prescribing alerts. These resources frequently describe different portions of an interaction while using incompatible entities, relation types, temporal assumptions, evidence labels, and levels of causal interpretation. Consequently, a molecular perturbation may be represented as equivalent to an exposure change, a predicted association may appear indistinguishable from an observed interaction, and a pairwise alert may omit the dose, timing, patient state, or physiological process that determines its relevance. This article proposes a causal grammar for representing drug–drug interactions as evidence-bearing chains extending from a context-specific molecular initiation event through enzymes, transporters, disposition processes, systemic or tissue exposure changes, and bounded clinical consequences. The grammar distinguishes interacting-drug roles, molecular mechanisms, biological mediators, pharmacokinetic transitions, contextual qualifiers, evidence assertions, contradictions, uncertainty, and applicability boundaries. It is designed to preserve direction, magnitude, temporal sequence, dose and regimen conditions, anatomical location, genotype, current metabolic phenotype, organ function, inflammation, and other patient-specific modifiers without reducing them to a single interaction score. The proposed construct also separates molecular plausibility, computational prediction, mechanistic explanation, quantitative simulation, clinical observation, and decision relevance as different evidence states requiring different forms of validation. Its purpose is not to generate dosing recommendations or establish clinical causality autonomously, but to provide a coherent semantic architecture for evidence integration, mechanistic reasoning, model documentation, and context-aware decision support. The grammar remains conceptual and requires formal ontology testing, pharmacological adjudication, quantitative evaluation, interoperability assessment, and prospective human-centered validation before operational use.</p>
      </abstract>
      <kwd-group>
                <kwd>Drug–drug interaction</kwd>
                <kwd>Causal ontology</kwd>
                <kwd>Pharmacokinetics</kwd>
                <kwd>Drug metabolism</kwd>
                <kwd>Membrane transporters</kwd>
                <kwd>Knowledge graph</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>