How the body processes medicines

First pass

A swallowed tablet passes the gut wall and the liver before the rest of the body, and both remove part of the dose ¹².

Enterocytes and hepatocytes both express CYP3A4 ¹.

Oxidation by cytochrome P450

One enzyme family, cytochrome P450, performs most of the oxidation of medicines ³.

Each P450 of the endoplasmic reticulum membrane inserts one oxygen atom into its substrate and reduces the second to water, with two electrons from NADPH through cytochrome P450 oxidoreductase ⁴. Of 4192 reported oxidation and reduction reactions of 860 drugs, about 96% were P450 reactions: CYP3A4 27%, CYP2D6 13%, CYP2C9 10%, CYP2C19 and CYP1A2 9% each, CYP2E1 3% ³. CYP2E1, with CYP1A2 and CYP2A6, oxidises paracetamol to the reactive imine NAPQI, 5% to 10% of its urinary metabolites ⁵.

Conjugation

Other enzymes attach a water-soluble group, so bile or urine can remove the drug ⁴.

UGTs transfer glucuronic acid from UDP-glucuronate, sulfotransferases a sulfonate group from PAPS, NAT2 an acetyl group from acetyl-CoA and TPMT a methyl group from S-adenosylmethionine ⁴. TPMT methylates the mercaptopurine formed from azathioprine; 1 in 300 people of European or African ancestry have almost no TPMT activity ⁶.

Transporters

Transport proteins move drugs into and out of gut, liver and kidney cells ⁴.

OATP1B1 (SLCO1B1) takes organic anions, statins among them, into the hepatocyte across its basolateral membrane; P-glycoprotein (ABCB1) and BCRP (ABCG2) pump drugs out across apical membranes ⁴. In 8 volunteers, 10 days of rifampicin 600 mg daily raised duodenal P-glycoprotein 3.5-fold and lowered the peak concentration of 1 mg oral digoxin by 58% ².

Induction and inhibition

Other medicines and some foods change the amount or activity of these proteins, and so the effect of a dose ⁷¹.

Rifampicin induces CYP1A2, CYP2C19, CYP3A4 and three further P450s, UGTs, sulfotransferases, carboxylesterases, P-glycoprotein and MRP2; oxycodone exposure falls by 86% ⁷. Grapefruit juice acts the other way: in 10 men, 8 oz of it three times daily for 6 days lowered enterocyte CYP3A4 protein by 62%, hepatic activity unchanged, and with the first glass felodipine peaked at 17.9 nmol/l against 5.5 with water ¹. Omeprazole inhibits CYP2C19 and lowers the active metabolite of clopidogrel, and the FDA advises against the pair ⁸.

Inherited differences

People differ in the speed of these steps, partly by inheritance ⁹.

Codeine is a prodrug: CYP2D6 O-demethylates 5% to 10% of a dose to morphine; UGT2B7 and UGT2B4 conjugate 70% to 80% to codeine-6-glucuronide ⁹. Duplication of CYP2D6 gives ultrarapid metabolism, 1% to 10% of white Europeans and North Americans; children have died of respiratory depression, and codeine is contraindicated below 12 years ⁹.

Activation of codeine by CYP2D6Hepatocyte endoplasmic reticulum membrane

Codeine
CYP2D6 (O-demethylation)O2, NADPH through cytochrome P450 oxidoreductase (POR)5% to 10% of the dose; 70% to 80% forms codeine-6-glucuronide
Morphine
UDP-glucuronosyltransferaseUDP-glucuronic acidAnalgesic in humans, unlike morphine-3-glucuronide
Morphine-6-glucuronide

Clopidogrel is a prodrug too: esterases hydrolyse about 85% of a dose to an inactive acid, and two oxidations, CYP2C19 prominent in both, yield the thiol that blocks P2Y12 irreversibly ¹⁰. Among 227 patients after coronary intervention, an ischaemic event or cardiovascular death within 1 year occurred in 20.9% of CYP2C19*2 carriers against 10.0% of others (hazard ratio 2.42, 95% CI 1.18 to 4.99) ¹¹.

Activation of clopidogrelAbsorbed in the intestine; oxidised on the hepatocyte endoplasmic reticulum membrane

Clopidogrel
CYP2C19, with CYP1A2 and CYP2B6O2, NADPH through cytochrome P450 oxidoreductase (POR)OmeprazoleEsterases hydrolyse 85% of the dose to an inactive acid
2-Oxo-clopidogrel
CYP2C19, with CYP3A4, CYP2C9 and CYP2B6O2, NADPH through cytochrome P450 oxidoreductase (POR)Omeprazole2-Oxo-clopidogrel is a thiolactone; ring opening frees the thiol
Active thiol metabolite
non-enzymatic binding to a free cysteine of P2RY12Irreversible; the platelet is affected for 7 to 10 days
Blocked P2Y12 receptor

References

Independent research
Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression Journal of Clinical Investigation, 1997.
doi:10.1172/JCI119439 PubMed 9153299
Funding and finding
Participants
15
Funding
This study was supported by NIH grants GM38149-11 (P.B. Watkins), GM53095-01 (K.S. Lown), MO1 RR00042 (University of Michigan General Clinical Research Center), and by a grant from the Medical Research Council of Canada (MA-11584).
In-kind support
Antibodies to CYP3A4 and CYP3A5 were gifts from a scientist at Eli Lilly and the antibody to CYP2D6 from a scientist at Merck Research Laboratories.
Finding
Ten inpatients drank 8 oz of grapefruit juice three times daily for 6 days. Enterocyte CYP3A4 protein fell by 62% (P = 0.0006) with no change in CYP3A4 mRNA, in hepatic CYP3A4 activity measured by the erythromycin breath test, in colonic CYP3A5 or in small-bowel P-glycoprotein, villin, CYP1A1 and CYP2D6. With the first glass, mean felodipine peak concentration rose from 5.5 ± 3.4 to 17.9 ± 3.3 nmol/l (an increase of 225%, P = 0.0001) and mean area under the curve over 12 hours from 35.3 ± 21.6 to 76.4 ± 15.6 nmol·h/l (an increase of 116%, P = 0.0001). With the 16th glass these values were 34% and 44% higher again. The increase ranged from 64% to 597% for the peak and from 4% to 368% for the area under the curve across the 10 subjects. Enterocyte CYP3A4 measured before the juice correlated with the rise in peak concentration (r = 0.67, P = 0.043).
Independent research
Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin Journal of Clinical Investigation, 1999.
doi:10.1172/JCI6663 PubMed 10411543
Funding and finding
Participants
8
Funding
This work was supported by grants from the Robert Bosch Foundation and the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (BMBF grant 01EC9405).
Finding
Rifampicin 600 mg daily for 10 days reduced the peak plasma concentration of 1 mg oral digoxin by 58% and oral bioavailability by 30.1%, and raised duodenal P-glycoprotein content 3.5 ± 2.1-fold. Systemic clearance after 1 mg intravenous digoxin rose 21%; renal clearance and half-life were unchanged. A 2002 correction (J Clin Invest 110:571) revises the correlation between AUC 0 to 144 h and P-glycoprotein content to Spearman rs 0.71 (P < 0.005), gives oral bioavailability as 44% or 49.5% depending on the intravenous AUC used, and states that the principal findings stand.
Independent research
Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals Chemical Research in Toxicology, 2015.
doi:10.1021/tx500444e PubMed 25485457
Funding and finding
Funding
This work was supported in part by National Institutes of Health Grants R37 CA090426, R01 ES010546, and R01 GM103937 (to F.P.G.). The authors declare no competing financial interest.
Finding
Counts of reported metabolic reactions from literature covering 1976 to 2008. Of 4192 oxidation and reduction reactions of 860 drugs, about 96% are catalysed by cytochrome P450 enzymes; flavin-containing monooxygenase, monoamine oxidase and aldo-keto reductase together account for about 5% across all chemicals. Shares of P450 reactions for drugs: CYP3A4 27%, CYP2D6 13%, CYP2C9 10%, CYP2C19 9%, CYP1A2 9%, CYP3A5 6%, CYP2C8 5%, CYP2B6 4%, CYP2E1 3%, other P450s 6%. CYP1A2, 2C9, 2C19, 2D6 and 3A4 with 3A5 account for 74%. Percentages count reported reactions, not prescriptions or clearance, and the authors call them estimates.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation (SERI); EMBL Australia. Funding for open access charge: National Institutes of Health. Conflict of interest statement: none declared.
Finding
Reviewed human entries read 2026-10-21 through rest.uniprot.org. CYP3A4 (P08684), CYP2D6 (P10635), CYP2C9 (P11712), CYP2C19 (P33261), CYP1A2 (P05177) and CYP2E1 (P05181) are cytochrome P450 monooxygenases of the endoplasmic reticulum membrane, CYP2E1 also of the mitochondrial inner membrane; each inserts one atom of molecular oxygen into a substrate and reduces the second to a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase, and each catalyses the hydroxylation of carbon-hydrogen bonds. CYP2D6 is also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists and tricyclic antidepressants; CYP2C19 in that of S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine; CYP2E1 in that of xenobiotics (probable). POR (P16435), NADPH-cytochrome P450 reductase, is required for electron transfer from NADP to cytochrome P450 in microsomes. UGT2B7 (P16662), of the endoplasmic reticulum membrane, conjugates lipophilic substrates with glucuronic acid, which increases the water solubility of the metabolite and so its excretion into urine or bile: glucuronate acceptor + UDP-alpha-D-glucuronate = acceptor beta-D-glucuronoside + UDP + H+. SULT1A1 (P50225) uses 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor for acceptors bearing a hydroxyl or amine group, a phenol + PAPS = an aryl sulfate + adenosine 3',5'-bisphosphate + H+, with broad specificity for small phenolic compounds and sulfate conjugation of xenobiotics including acetaminophen and minoxidil (by similarity); sulfonation raises water solubility and renal excretion of most compounds but can also bioactivate, as with carcinogenic N-hydroxyarylamines. NAT2 (P11245) catalyses the N- or O-acetylation of arylamine and heterocyclic amine substrates, an arylamine + acetyl-CoA = an N-acetylarylamine + CoA, and participates in the detoxification of hydrazine and arylamine drugs while bioactivating several known carcinogens. TPMT (P51580) catalyses the S-methylation of thiopurine drugs such as mercaptopurine and 6-thioguanine with S-adenosyl-L-methionine as methyl donor, and its activity modulates the cytotoxic effects of thiopurine prodrugs; no natural substrate has been identified. SLCO1B1 (Q9Y6L6, OATP1B1), of the basolateral hepatocyte membrane, mediates Na+-independent uptake of organic anions, among them taurocholate, conjugated steroids, eicosanoids, thyroid hormones, bilirubin glucuronides and HMG-CoA reductase inhibitors such as pravastatin and pitavastatin, with hydrogencarbonate the probable counteranion. ABCB1 (P08183, P-glycoprotein), of the apical cell membrane, is an energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells, translocates phospholipids and drugs across the membrane, and may contribute to hepatobiliary and renal excretion of etiocholanolone-3-glucuronate. ABCG2 (Q9UNQ0, BCRP), also of the apical cell membrane, is an ATP-dependent transporter of broad substrate specificity that extrudes physiological compounds, dietary toxins and xenobiotics, as well as urate, sulfate conjugates and protoporphyrin IX; it operates at the apical membranes of polarised cells such as hepatocytes and intestinal epithelial cells, where it may contribute to the efflux of conjugated substrates from intestine and liver into the intestinal lumen, and it exports urate in both renal and extrarenal urate excretion.
Textbook or database
Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses Pharmacogenetics and Genomics, 2015.
doi:10.1097/FPC.0000000000000150 PubMed 26049587
Funding and finding
Funding
This study is supported by the NIH/NIGMS R24 GM61374, The Personalized NSAID Therapeutics Consortium (PENTACON: HL117798) and by T32 H107971.
Finding
Oral bioavailability of paracetamol is 88% and the plasma half-life 1.5 to 2.5 hours at recommended doses. After a therapeutic dose, urinary metabolites are the glucuronide (52 to 57%), the sulfate (30 to 44%) and products of oxidation to N-acetyl-p-benzoquinone imine (NAPQI, 5 to 10%); less than 5% is excreted unchanged. UGT1A1, UGT1A6, UGT1A9 and UGT2B15 catalyse glucuronidation; SULT1A1 and SULT1A3/4 catalyse sulfation, with SULT1E1 and SULT2A1 in fetal liver; CYP2E1, with CYP1A2 and CYP2A6, forms NAPQI. NAPQI is conjugated with glutathione spontaneously and by glutathione S-transferases, GSTP1 being the most effective catalyst, followed by GSTT1 and GSTM1, and is excreted as cysteine and mercapturic acid conjugates. ABCC2 and ABCG2 of the canalicular membrane move the glucuronide and the sulfate into bile; movement of the glucuronide into blood depends on ABCC3 and that of the sulfate on ABCC3 with ABCC4, both of the sinusoidal membrane. Above 4 g per day sulfation saturates, and after highly toxic doses more than 15% is oxidised and about 10% excreted unchanged. The contribution of CYP3A4 is reported as ranging from negligible to primary.
Regulator
US Food and Drug Administration (labelling submitted by Legacy Pharma USA Inc.). IMURAN (azathioprine) 50 mg scored tablets: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 1, effective 19 March 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4d62b6e4-a9d4-4818-e063-6394a90aa208
Funding and finding
Funding
not stated; FDA-approved labelling carries no funding statement
Finding
Azathioprine is cleaved to 6-mercaptopurine, which hypoxanthine-guanine phosphoribosyltransferase and kinases convert to 6-thioguanine nucleotides; cytotoxicity follows in part from their incorporation into DNA. Mercaptopurine has two major inactivation routes: thiol methylation, catalysed by thiopurine S-methyltransferase (TPMT), to methyl-6-mercaptopurine, and oxidation, catalysed by xanthine oxidase, to 6-thiouric acid; NUDT15 converts 6-thioguanine nucleotides to inactive monophosphates. TPMT activity correlates inversely with 6-thioguanine nucleotide concentrations in erythrocytes, which have negligible xanthine oxidase activity. About 0.3%, or 1 in 300, of patients of European or African ancestry carry two loss-of-function TPMT alleles and have little or no TPMT activity, and about 10% carry one, giving intermediate activity. Patients with reduced TPMT or NUDT15 activity given usual doses accumulate 6-thioguanine nucleotides and are at higher risk of severe myelosuppression, and those with TPMT or NUDT15 deficiency require alternative therapy or dose modification.
Regulator
US Food and Drug Administration (labelling submitted by ANI Pharmaceuticals, Inc.). Rifampin capsules, USP: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 1, effective 10 October 2024, 2024.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b389b1a3-672f-47e3-916c-4a9c044b211b
Funding and finding
Funding
not stated; FDA-approved labelling carries no funding statement
Finding
Rifampin is a well characterised and potent inducer of drug metabolising enzymes and transporters. Those affected include cytochromes P450 1A2, 2B6, 2C8, 2C9, 2C19 and 3A4, UDP-glucuronyltransferases, sulfotransferases, carboxylesterases, P-glycoprotein and multidrug resistance-associated protein 2. Rifampin may therefore increase the metabolism and decrease the activity of a coadministered drug, or increase the activity of a coadministered prodrug that requires metabolic activation. Reductions in exposure listed in Table 1 include oxycodone and tamoxifen, area under the curve lowered by 86%, lenacapavir 84%, zopiclone 82%, daclatasvir 79%, zolpidem 73%, rosiglitazone 66%, cabotegravir 59%, tacrolimus 56% and losartan 30%; haloperidol plasma concentrations fall by 70%. For digoxin the label advises measuring serum concentrations before rifampin is started and raising the digoxin dose by about 20% to 40% as necessary. Concomitant use with clopidogrel should be discouraged, because the exposure to the active metabolite and the risk of bleeding increase.
Regulator
US Food and Drug Administration. FDA reminder to avoid concomitant use of Plavix (clopidogrel) and omeprazole US Food and Drug Administration, posted 27 October 2010, 2010.
http://web.archive.org/web/20171104220627/https://www.fda.gov/Drugs/DrugSafety/ucm231161.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
FDA continues to warn against concomitant use of clopidogrel and omeprazole because co-administration can significantly reduce levels of the active metabolite of clopidogrel and its antiplatelet activity; the warning was added to the Plavix label in November 2009. The recommendation applies only to omeprazole, not to all PPIs, because PPIs differ in inhibition of CYP2C19; pantoprazole, a weak CYP2C19 inhibitor, may be an alternative.
Regulator
US Food and Drug Administration (labelling submitted by Lannett Company, Inc.). Codeine sulfate tablets, USP, for oral use: full prescribing information US Food and Drug Administration approved prescribing information, via DailyMed; version 29, effective 16 January 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5819bdf7-300e-45b8-8f3a-447b53656293
Funding and finding
Funding
not stated; FDA-approved labelling carries no funding statement
Finding
Metabolism: about 70% to 80% of a codeine dose is conjugated with glucuronic acid to codeine-6-glucuronide, about 5% to 10% is O-demethylated to morphine and about 10% is N-demethylated to norcodeine. UGT2B7 and UGT2B4 are the major enzymes of the glucuronidation, CYP2D6 of the conversion to morphine and CYP3A4 of the conversion to norcodeine. Morphine and norcodeine are further conjugated with glucuronic acid; morphine-6-glucuronide has analgesic activity in humans and morphine-3-glucuronide is not considered to have it. About 90% of the dose is excreted renally, about 10% of it as unchanged codeine, and the plasma half-lives of codeine and its metabolites are about 3 hours. Peak plasma concentration occurs 60 minutes after an oral dose; plasma protein binding is 7% to 25%. Ultrarapid metabolisers carry CYP2D6 gene duplications such as *1/*1xN or *1/*2xN; the estimated prevalence of this phenotype is 1% to 10% for Whites (European, North American), 3% to 4% for Blacks (African Americans), 1% to 2% for East Asians (Chinese, Japanese, Korean) and above 10% in certain groups (Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). Life-threatening respiratory depression and death have occurred in children given codeine, most cases after tonsillectomy or adenoidectomy and many in ultrarapid metabolisers; the drug is contraindicated in children younger than 12 years and, for post-operative use, in those younger than 18 years after tonsillectomy or adenoidectomy, and breastfeeding is not recommended during treatment.
Textbook or database
Sangkuhl K, Klein TE, Altman RB. Clopidogrel pathway Pharmacogenetics and Genomics, 2010.
doi:10.1097/FPC.0b013e3283385420 PubMed 20440227
Funding and finding
Funding
PharmGKB is supported by the NIH/NIGMS Pharmacogenetics Research Network (PGRN; UO1GM61374).
Finding
Clopidogrel is a prodrug absorbed in the intestine and activated in the liver by two sequential oxidative steps, the first forming 2-oxo-clopidogrel and the second the active metabolite. CYP1A2, CYP2B6 and CYP2C19 form 2-oxo-clopidogrel from clopidogrel in liver microsomes; with 2-oxo-clopidogrel as substrate, CYP3A4, CYP2C9, CYP2C19 and CYP2B6 produce the active metabolite. Kazui and colleagues concluded that CYP2C19 contributes substantially to both steps and CYP3A4 to the second. In a competing reaction about 85% of the drug is hydrolysed by esterases to an inactive carboxylic acid. The thiol group of the active metabolite binds a free cysteine of the P2Y12 receptor (P2RY12) and irreversibly blocks ADP binding, so the platelet is affected for its whole lifespan of about 7 to 10 days. Clopidogrel is not detected in human plasma. Between 20% and 40% of patients show low inhibition of ADP-induced platelet aggregation. ABCB1 takes part in intestinal absorption. Interactions have been reported with atorvastatin, verapamil and omeprazole.
Independent research
Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy JAMA, 2009.
doi:10.1001/jama.2009.1232 PubMed 19706858
Funding and finding
Participants
656
Follow-up
1 year in the percutaneous coronary intervention sample
Funding
National Institutes of Health grants U01 GM074518 and U01 HL084756, the Clinical Nutrition Research Unit of Maryland (P30 DK072488), the University of Maryland General Clinical Research Center (M01 RR 16500), the Baltimore Veterans Administration Geriatric Research and Education Clinical Center, and Sinai Hospital of Baltimore. The funding organizations had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
Finding
Platelet response to clopidogrel was heritable (h2 = 0.73, P < 0.001). Thirteen single-nucleotide polymorphisms in the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster on chromosome 10q24 were associated with diminished response; rs12777823, in strong linkage disequilibrium with CYP2C19*2, accounted for 12% of the variation in ADP-stimulated platelet aggregation (P = 4.3 × 10-11). Among 227 patients after percutaneous coronary intervention, a cardiovascular ischaemic event or death occurred within 1 year in 20.9% of CYP2C19*2 carriers and 10.0% of non-carriers (hazard ratio 2.42, 95% CI 1.18 to 4.99; P = 0.02), an absolute difference of 10.9 percentage points.
Expert consensus
Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED, Gaedigk A, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy Clinical Pharmacology and Therapeutics, 2021.
doi:10.1002/cpt.2149 PubMed 33387367
Funding and finding
Funding
This work was funded by the National Institutes of Health (NIH) for CPIC (U24HG010135) and PharmGKB (U24HG010615), with additional NIH support (R24 GM123930, U01 HG007269, UL1 TR001427, U01 HG010245, R01 DA042985, U01 HG8666, R35 GM124939, UL1 TR001082) and grants from the National Health and Medical Research Council of Australia (1011251) and the Indiana University Grand Challenge Precision Health Initiative.
Finding
Each CYP2D6 allele is assigned an activity value from 0 to 1, multiplied by copy number where a functional gene is duplicated, and the values of the two alleles are summed into an activity score, which typically ranges from 0 to 3. Phenotypes: ultrarapid metaboliser above 2.25, normal 1.25 to 2.25, intermediate above 0 and below 1.25, poor 0. Codeine and tramadol are O-demethylated by CYP2D6 to the more active metabolites morphine and O-desmethyltramadol. Pharmacokinetic studies found 96% lower mean serum morphine area under the curve and 95% lower peak concentration in poor metabolisers than in normal and intermediate metabolisers, and 45% higher median morphine area under the curve in ultrarapid than in normal metabolisers. Codeine recommendations: avoid in ultrarapid metabolisers because of the potential for serious toxicity and in poor metabolisers because of possible diminished analgesia, both strong; use label-recommended dosing in normal metabolisers (strong) and in intermediate metabolisers (moderate). Tramadol recommendations follow the same pattern. For hydrocodone in ultrarapid metabolisers no recommendation is given. Variation among individuals carrying the same diplotype is large and its genomic or environmental causes are unknown.
Expert consensus
Lee CR, Luzum JA, Sangkuhl K, Gammal RS, Sabatine MS, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update Clinical Pharmacology and Therapeutics, 2022.
doi:10.1002/cpt.2526 PubMed 35034351
Funding and finding
Funding
This work was funded by the National Institutes of Health (NIH) for CPIC (R24GM115264 and U24HG010135), PharmGKB (U24HG010615) and PharmVar (R24 GM123930), with additional NIH grants to individual authors (R01HL149752, K08HL146990, UL1TR003098, R35GM131770, R01HL092173, K24HL133373).
Finding
Clopidogrel is a thienopyridine prodrug. Only 15% of the dose is available for transformation to the active agent, the remaining 85% being hydrolysed by carboxylesterase-1 to inactive forms. Conversion requires two sequential oxidative steps involving CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5, with the greatest contribution from CYP2C19 in both steps; the active metabolite selectively and irreversibly inhibits the P2Y12 receptor for the platelet lifespan of about 10 days. For acute coronary syndrome or percutaneous coronary intervention, CYP2C19 intermediate and poor metabolisers should avoid standard-dose clopidogrel and receive prasugrel or ticagrelor where not contraindicated (strong for both phenotypes); normal, rapid and ultrarapid metabolisers should receive the standard 75 mg daily dose (strong). In a meta-analysis of seven randomised trials of genotype-guided antiplatelet therapy with 15,949 patients (77% percutaneous coronary intervention, 98% acute coronary syndrome), prasugrel or ticagrelor reduced major ischaemic events against clopidogrel in intermediate and poor metabolisers (risk ratio 0.70, 95% CI 0.59 to 0.83) but not in non-carriers of no-function alleles (risk ratio 1.0, 95% CI 0.80 to 1.25), with a genotype-treatment interaction at P = 0.013.
Industry-funded
Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease New England Journal of Medicine, 2010.
doi:10.1056/NEJMoa1007964 PubMed 20925534
Funding and finding
Registration
NCT00557921
Participants
3,873
Follow-up
event rates at 180 days; terminated early when the sponsor lost financing
Funding
Funded by Cogentus Pharmaceuticals (statement in the abstract). Registry NCT00557921: lead sponsor Cogentus Pharmaceuticals; responsible party Pablo Lapuerta, Cogentus Pharmaceuticals, an author; intervention CGT-2168, clopidogrel 75 mg with omeprazole 20 mg, against clopidogrel 75 mg; terminated by the sponsor.
Finding
Gastrointestinal events 1.1% with omeprazole against 2.9% with placebo at 180 days (HR 0.34, 95% CI 0.18 to 0.63); overt upper gastrointestinal bleeding HR 0.13 (0.03 to 0.56). Cardiovascular events 4.9% against 5.7% (HR 0.99, 0.68 to 1.44). Diarrhoea was more frequent with omeprazole.
Industry-funded
Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, Scheidel B, Jakob V, Rodamer M, et al. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrobial Agents and Chemotherapy, 2005.
doi:10.1128/AAC.49.5.1733-1738.2005 PubMed 15855489
Funding and finding
Participants
18
Funding
The study was supported by a grant by Fatol Arzneimittel GmbH, Schiffweiler, Germany.
In-kind support
Both oral preparations given, ISOZID and ISOZID COMP. N, are products of the funding company.
Finding
Isoniazid is metabolised by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). NAT2 genotype, drug formulation and body weight together explained 93% of the variability in apparent isoniazid clearance, and NAT2 genotype alone 88%. Individual clearance was predicted as clearance in litres per hour = 10 + 9 × the number of high-activity NAT2*4 alleles. To reach similar exposure, standard doses suited to one high-activity allele would be lowered or raised by about 50% for carriers of none or of two. The authors state that prospective clinical trials are required to assess the merits of this approach.
Independent research
Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel CMAJ (Canadian Medical Association Journal), 2009.
doi:10.1503/cmaj.082001 PubMed 19176635
Funding and finding
Participants
13,636
Follow-up
90 days after discharge; secondary analysis 1 year
Funding
This study was supported by the Ontario Ministry of Health and Long-Term Care, the Canadian Institutes of Health Research (CIHR) and a CIHR Team Grant in Cardiovascular Outcomes Research; authors held awards from CIHR, the Heart and Stroke Foundation of Ontario and a Canada Research Chair.
Finding
Clopidogrel is a prodrug converted in the liver, chiefly by CYP2C19, to a thiol metabolite that irreversibly inhibits the platelet P2Y12 receptor. Current PPI use was associated with reinfarction within 90 days (adjusted OR 1.27, 95% CI 1.03 to 1.57); pantoprazole was not (1.02, 0.70 to 1.47), whereas omeprazole, lansoprazole and rabeprazole together were (1.40, 1.10 to 1.77). H2-receptor antagonists and PPI use in patients not taking clopidogrel were not associated with reinfarction.

Updated 2026-10-21