Editing Drug interaction (section)

== Interactions based on pharmacokinetics ==
[[Pharmacokinetics]] is the field of research studying the chemical and biochemical factors that directly affect [[Dosage form|dosage]] and the [[half-life]] of drugs in an organism, including absorption, transport, distribution, metabolism and excretion. Compounds may affect any of those process, ultimately interfering with the flux of drugs in the [[human body]], increasing or reducing drug availability. 

=== Based on absorption ===
Drugs that change intestinal motility may impact the level of other drugs taken. For example, [[Prokinetic agent|prokinetic agents]] increase the [[intestinal motility]], which may cause drugs to go through the digestive system too fast, reducing absorption. {{Citation needed|date=November 2023}}

The pharmacological modification of [[pH]] can affect other compounds. Drugs can be present in ionized or [[Electrically neutral|non-ionized]] forms depending on [[pKa]], and neutral compounds are usually better absorbed by membranes.<ref name="Malgor - Valsecia">Malgor — Valsecia, ''Farmacología general: Farmacocinética.''Cap. 2. en {{cite web |url=http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |title=Archived copy |access-date=2012-03-20 |url-status=dead |archive-url=https://web.archive.org/web/20120907035648/http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |archive-date=2012-09-07 }} Revised 25 September 2008</ref> Medication like [[antacid]]s can increase pH and inhibit the absorption of other drugs such as [[zalcitabine]], [[tipranavir]] and [[amprenavir]]. The opposite is more common, with, for example, the antacid [[cimetidine]] ''stimulating'' the absorption of [[didanosine]]. Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction.<ref>Alicia Gutierrez Valanvia y Luis F. López-Cortés ''Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales.'' on [http://artigos.tol.pro.br/portal/linguagem-es/interacción%20farmacológica] accessed 24 September 2008</ref>

Factors such as food with [[Fat|high-fat content]] may also alter the solubility of drugs and impact its absorption. This is the case for oral [[anticoagulant]]s and [[avocado]].{{Citation needed|date=November 2023}} The formation of non-absorbable complexes may occur also via [[chelation]], when [[Ion|cation]]s can make certain drugs harder to absorb, for example between [[tetracycline]] or the [[Quinolone antibiotic|fluoroquinolone]]s and dairy products, due to the presence of [[calcium ions]].{{Citation needed|date=November 2023}} .  Other drugs bind to proteins. Some drugs such as [[sucralfate]] bind to proteins, especially if they have a high [[bioavailability]]. For this reason its administration is [[contraindicated]] in [[Feeding tube|enteral feeding]].<ref name="Marduga">Marduga Sanz, Mariano. ''Interacciones de los alimentos con los medicamentos''. on [http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf] {{Webarchive|url=https://web.archive.org/web/20140707212321/http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf|date=2014-07-07}}</ref>

Some drugs also alter absorption by acting on the [[P-glycoprotein]] of the [[enterocyte]]s. This appears to be one of the mechanisms by which [[grapefruit]] juice increases the [[bioavailability]] of various drugs beyond its inhibitory activity on [[first pass effect|first pass metabolism]].<ref>Tatro, DS. ''Update: Drug interaction with grapefruit juice.'' Druglink, 2004. 8 (5), page 35ss</ref>

=== Based on transport and distribution===
Drugs also may affect each other by competing for transport proteins in [[Blood plasma|plasma]], such as [[albumin]]. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, modifying its expected concentration. The organism has mechanisms to counteract these situations (by, for example, increasing [[Clearance (medicine)|plasma clearance]]), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion.<ref>[https://web.archive.org/web/20040619231334/http://www.biologia.edu.ar/farmacologia/clas2do%5Cinteraccion_03.pdf Valsecia, Mabel en]</ref>

=== Based on metabolism ===
[[File:CYP2C9 1OG2.png|thumb|200px|Diagram of cytochrome P450 [[CYP2C9|isoenzyme 2C9]] with the [[heme|haem]] group in the centre of the enzyme.]]

Many drug interactions are due to alterations in [[drug metabolism]].<ref name=GENENG15June2008>{{cite news | author=Elizabeth Lipp
 | title=Tackling Drug-Interaction Issues Early On | url=http://www.genengnews.com/articles/chitem.aspx?aid=2509
 | work=[[Genetic Engineering & Biotechnology News]] | publisher=[[Mary Ann Liebert, Inc.]] | pages=14, 16, 18, 20
 | date=2008-06-15 | access-date=2008-07-06
 | quote=(subtitle) Researchers explore a number of strategies to better predict drug responses in the clinic }}</ref> Further, human drug-metabolizing enzymes are typically activated through the engagement of [[nuclear receptor]]s.<ref name=GENENG15June2008/> One notable system involved in metabolic drug interactions is the enzyme system comprising the [[cytochrome P450 oxidase]]s.

==== CYP450 ====
[[Cytochrome P450]] is a very large family of [[hemeprotein|haemoprotein]]s (hemoproteins) that are characterized by their [[enzyme|enzymatic]] activity and their role in the metabolism of a large number of drugs.<ref>{{GoldBookRef|title=cytochrome P450|file=CT06821}} {{cite journal | vauthors = Danielson PB | title = The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans | journal = Current Drug Metabolism | volume = 3 | issue = 6 | pages = 561–97 | date = December 2002 | pmid = 12369887 | doi = 10.2174/1389200023337054 }}</ref> Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]] and [[CYP3A4]].<ref name="Nelson">Nelson D (2003). [http://drnelson.utmem.edu/P450lect.html Cytochrome P450s in humans] {{webarchive |url=https://web.archive.org/web/20090710050953/http://drnelson.utmem.edu/P450lect.html |date=July 10, 2009 }}. Consulted 9 May 2005.</ref>
The majority of the enzymes are also involved in the metabolism of [[endogenous]] substances, such as [[steroid]]s or [[sex hormones]], which is also important should there be interference with these substances. The function of the enzymes can either be stimulated ([[enzyme induction]]) or inhibited ([[enzyme inhibition]]).

==== Through enzymatic inhibition and induction ====
If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration.{{Citation needed|date=November 2023}}

In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect.{{Citation needed|date=November 2023}}

Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism. 

==== Examples of metabolism-based interactions ====
An example of this is shown in the following table for the [[CYP1A2]] enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity:<ref name="Nelson" />

{| class="wikitable" style="margin:1em auto;" width="100%"
|-
| colspan="3" style="text-align:center;" | '''Drugs related to CYP1A2'''
|-
! Substrates !! Inhibitors !! Inductors
|- style="vertical-align: top;"
|
* [[Caffeine]]
* [[Theophylline]]
* [[Phenacetin]]
* [[Clomipramine]]
* [[Clozapine]]
* [[Thioridazine]]
||
* [[Omeprazole]]
* [[Nicotine]]
* [[Cimetidine]]
* [[Ciprofloxacin]]
||
* [[Phenobarbital]]
* [[Fluvoxamine]]
* [[Venlafaxine]]
* [[Ticlopidine]]
|}

Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:
{| class="wikitable" style="margin:1em auto;" width=100%
|-
|colspan="3" style="text-align:center;"| Foods and their influence on drug metabolism<ref>{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–10 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}<br/>Comment in: {{cite journal | vauthors = Mouly S, Paine MF | title = Effect of grapefruit juice on the disposition of omeprazole | journal = British Journal of Clinical Pharmacology | volume = 52 | issue = 2 | pages = 216–7 | date = August 2001 | pmid = 11488783 | pmc = 2014525 | doi = 10.1111/j.1365-2125.1978.00999.pp.x }}{{Dead link|date=January 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Marduga" /><ref>{{cite journal |author=Covarrubias-Gómez, A. |title=¿Qué se auto-administra su paciente?: Interacciones farmacológicas de la medicina herbal |journal=Revista Mexicana de Anestesiología |volume=28 |issue=1 |pages=32–42 |date=January–March 2005 |url=http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |archive-url=https://archive.today/20120629232743/http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |url-status=dead |archive-date=2012-06-29 |display-authors=etal }}</ref>
|-
! Food !! Mechanism !! Drugs affected
|-
|
* [[Avocado]]
* [[Brassicaceae|Brassica]]s (Brussels sprouts, broccoli, cabbage)
|Enzymatic inductor
|[[Acenocoumarol]], [[warfarin]]
|-
|[[Grapefruit]] juice
|Enzymatic inhibition
|
* [[Calcium channel blocker]]s: [[nifedipine]], [[felodipine]], [[nimodipine]], [[amlodipine]]
* [[Cyclosporine]], [[tacrolimus]]
* [[Terfenadine]], [[astemizole]]
* [[Cisapride]], [[pimozide]]
* [[Carbamazepine]], [[saquinavir]], [[midazolam]], [[alprazolam]], [[triazolam]]
{{main|Grapefruit drug interactions}}
|-
|[[Soybean|Soya]]
|Enzymatic inhibition
|[[Clozapine]], [[haloperidol]], [[olanzapine]], [[caffeine]], [[Non-steroidal anti-inflammatory drug|NSAIDs]], [[phenytoin]], [[zafirlukast]], [[warfarin]]
|-
|[[Garlic]]
|Increases antiplatelet activity
|
* [[Anticoagulant]]s
* [[Non-steroidal anti-inflammatory drug|NSAIDs]], [[acetylsalicylic acid]]
|-
|[[Ginseng]]
|To be determined
|[[Warfarin]], [[heparin]], [[aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAIDs]]
|-
|''[[Ginkgo biloba]]''
|Strong inhibitor of platelet aggregation factor
|[[Warfarin]], [[aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAIDs]]
|-
|''[[Hypericum perforatum]]'' (St John's wort)
|Enzymatic inductor (CYP450)
|Warfarin, [[digoxin]], [[theophylline]], cyclosporine, [[phenytoin]] and antiretrovirals
|-
|[[Ephedra (medicine)|Ephedra]]
|Receptor level agonist
|[[MAOI]], central nervous system stimulants, alkaloids [[ergotamine]]s and [[xanthine]]s
|-
|Kava (''Piper methysticum'')
|Unknown
|[[Levodopa]]
|-
|[[Ginger]]
|Inhibits thromboxane synthetase (''in vitro'')
|Anticoagulants
|-
|Chamomile
|Unknown
|[[Benzodiazepine]]s, [[barbiturate]]s and [[opioid]]s
|-
|[[Crataegus|Hawthorn]]
|Unknown
|Beta-adrenergic antagonists, [[cisapride]], digoxin, [[quinidine]]
|}

=== Based on excretion ===

==== Renal and biliary excretion ====
Drugs tightly bound to proteins (i.e. not in the [[free fraction]]) are not available for [[renal excretion]].<ref name="Gago6">Gago Bádenas, F. ''Curso de Farmacología General. Tema 6.- Excreción de los fármacos''. en [http://www2.uah.es/farmamol/Public/PDF_files/Farma_3M_tema6.pdf] {{Webarchive|url=https://web.archive.org/web/20110916225410/http://www2.uah.es/farmamol/Public/PDF_files/Farma_3M_tema6.pdf|date=2011-09-16}}</ref>
Filtration depends on a number of factors including the [[pH]] of the urine. Drug interactions may affect those points. {{Citation needed|date=November 2023}}