Drug Metabolism and Aging

Older adults often respond differently to medications than younger people. The same dose can lead to higher drug levels, stronger effects and more side effects. This happens because aging changes how the body absorbs, distributes, breaks down and removes drugs, and because older adults are more sensitive to many medications. Many seniors also take several medications at once, and inherited differences in drug-metabolizing genes add another layer of variability. This article explains these changes and what they mean for safe prescribing.

What happens to a drug in the body?

Once a medication enters the body, it goes through four steps, known as ADME:

• Absorption: the drug enters the bloodstream, usually from the small intestine for pills.
• Distribution: the drug travels through the blood to the tissues where it acts.
• Metabolism: the drug is chemically changed, mostly by liver enzymes, so it can be removed.
• Excretion: the drug or its breakdown products leave the body, mainly in urine or bile.

Aging affects each step, and the overall result is usually slower clearance, longer-lasting drug effects and greater differences between individuals.

How does aging affect absorption?

With age, the stomach empties more slowly and blood flow to the intestine decreases, so some drugs may take longer to reach the bloodstream. However, the total amount of most drugs absorbed changes little with age. Food, antacids and other medications that change stomach acidity often matter more. This is why some medications must be taken with food or on an empty stomach.

How does aging affect distribution?

As we age, body fat increases and total body water decreases:

• Fat-soluble drugs, such as diazepam and many other sedatives, spread into the extra fat and stay in the body longer, so their effects can last much longer.
• Water-soluble drugs, such as lithium, digoxin and alcohol, are concentrated in a smaller volume of body water, so blood levels can be higher after the same dose.

Levels of albumin, the main protein that carries drugs such as warfarin and phenytoin in the blood, can fall in older adults who are frail or ill. This can increase the amount of free, active drug.

How does aging affect drug metabolism in the liver?

Of all the age-related changes, those in the liver often have the greatest effect on medications. With age, liver size and blood flow to the liver decrease, by up to about 40% in older adults. This affects drugs in two ways:

• Drugs that depend on liver blood flow, such as propranolol, morphine, verapamil and some tricyclic antidepressants, are normally cleared quickly on their first pass through the liver. With less blood flow, more of each dose reaches the bloodstream, so lower doses may be needed.
• Drugs that depend on liver enzyme activity, such as diazepam, warfarin and phenytoin, are cleared more slowly when enzyme capacity falls with age, illness, frailty or interacting medications.

Some medications are inactive until the liver converts them into their active form. Examples include codeine and tramadol, which are activated by CYP2D6, and clopidogrel, which is activated by CYP2C19. For these drugs, reduced enzyme activity can mean less benefit rather than more side effects.

How does aging affect the kidneys?

Kidney function declines gradually with age, and many older adults have reduced kidney function even when routine blood tests look normal. Drugs cleared mainly by the kidneys can build up and often need lower doses. Examples include lithium, digoxin, metformin, gabapentin and pregabalin, some blood thinners such as dabigatran, allopurinol and many antibiotics. Dehydration and illness can reduce kidney function further.

How does menopause affect drug metabolism in women?

Women experience adverse drug reactions about twice as often as men, partly because sex hormones affect how drugs are absorbed, distributed and broken down. A 2025 review describes how estrogen influences several drug-metabolizing enzymes, including CYP1A2, CYP2C19, CYP3A4 and the UGT enzymes, as well as the P-glycoprotein drug transporter. When estrogen levels fall at menopause, the activity of these pathways can shift, and drug levels may change even when the dose stays the same. Changes in body composition after menopause, with more body fat and less muscle and body water, add to these effects.

Estrogen-containing hormone therapy can have the opposite effect. Estrogen increases the clearance of lamotrigine, so starting or stopping hormone therapy may require monitoring and dose changes for this seizure and mood medication. Oral estrogens can also slow CYP1A2 and raise levels of drugs such as clozapine, olanzapine and duloxetine. Women going through menopause, or starting or stopping hormone therapy, should ask their prescriber or pharmacist whether any of their medications need monitoring. Read more in Drug metabolism in women: the effects of pregnancy, contraception and hormone replacement therapy and Precision medicine of menopause and depression.

Why are older adults more sensitive to medications?

Aging changes not only drug levels but also how the body responds to them. Older adults are often more sensitive to sedatives, opioids, anticoagulants, blood pressure medications and drugs with anticholinergic effects. These can cause confusion, dizziness, falls, bleeding or low blood pressure at doses that younger adults tolerate well. Read more in Which medications can cause falls in the elderly?

Taking several medications at once (polypharmacy) increases the risk of drug interactions and side effects. The 2023 American Geriatrics Society Beers Criteria list medications that are usually best avoided or used with caution in adults 65 and older.

Are older adults at higher risk of drug-induced heart rhythm problems?

Yes. Many common medications can prolong the QT interval, a measure of how long the heart takes to recharge between beats. These include some antidepressants such as citalopram, antipsychotics, antibiotics such as clarithromycin, anti-nausea drugs and heart rhythm medications. In rare cases, QT prolongation can trigger a dangerous heart rhythm called torsades de pointes. Older adults are at higher risk because they often take several QT-prolonging drugs at once, clear many of them more slowly, and are more likely to have dehydration or low potassium and magnesium levels, for example from diuretics, vomiting or diarrhea.

Genes can add to this risk. Inherited variants in heart ion channel genes, such as the common KCNE1 D85N variant, reduce the heart's safety margin and have strong evidence for increasing the risk of drug-induced QT prolongation. Read more in Could your genes put you at risk for drug-induced heart arrhythmia?

How do genes and aging interact?

Many medications are broken down by cytochrome P450 (CYP) enzymes, and inherited differences in CYP genes make people poor, intermediate, normal, rapid or ultrarapid metabolizers. Aging can reduce the activity of some CYP enzymes more than others, so genes and age can combine in different ways:

• CYP2C19 and omeprazole. In a study of young and older adults, omeprazole clearance was much lower in older people. Some older normal metabolizers cleared omeprazole almost as slowly as poor metabolizers, showing that age can add to or mimic the effect of genes.
• CYP2C9 and anti-inflammatory drugs. A small 2003 study found no effect of age on celecoxib and diclofenac levels in healthy adults up to 75 years. Larger studies since then have shown that CYP2C9 poor metabolizers have much higher levels of celecoxib and some other anti-inflammatory drugs, and the CPIC guideline recommends lower doses or alternatives for them.
• Warfarin. Age, body weight and the CYP2C9 and VKORC1 genes all affect the warfarin dose. In a study of Chinese patients, these four factors together explained 63% of the differences in dose between patients, with VKORC1 alone explaining about half. Older adults generally need lower warfarin doses.

For an older adult who is also a poor metabolizer, the effects of age and genes can add up, increasing the risk of side effects. Reduced enzyme activity from liver disease or interacting medications can do the same.

Which medications need extra care in older adults?

• Benzodiazepines and other sleeping pills, which increase the risk of confusion and falls.
• Opioids such as codeine, tramadol and oxycodone.
• Blood thinners such as warfarin and dabigatran.
• Antidepressants and antipsychotics, especially those with sedating or anticholinergic effects.
• Anti-inflammatory painkillers (NSAIDs), which can affect the stomach, kidneys and blood pressure.
• Medications cleared by the kidneys, such as lithium, digoxin and metformin.

Regular medication reviews with a doctor or pharmacist help keep treatment safe as health and kidney function change over time.

Can a pharmacogenetic test help older adults?

A Pillcheck test shows how your genes affect many of the medications commonly used by older adults, including antidepressants, antipsychotics, opioids, blood thinners, heart medications and anti-inflammatory drugs. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. A Pillcheck pharmacist reviews your results together with all your medications and recommends safer options and doses to discuss with your prescriber. Because genes do not change, the results remain useful as new medications are added. Read more about optimizing medication plans for seniors with dementia.

Summary

• Aging slows how the liver and kidneys clear many medications, so the same dose can lead to higher drug levels.
• More body fat and less body water change how long drugs stay in the body and how concentrated they become.
• In women, falling estrogen at menopause, and starting or stopping hormone therapy, can change the activity of drug-metabolizing enzymes and the levels of drugs such as lamotrigine.
• Older adults are more sensitive to sedatives, opioids, blood thinners and blood pressure medications.
• Older adults are at higher risk of drug-induced heart rhythm problems because of multiple QT-prolonging drugs, dehydration and low potassium, especially if they carry variants in genes such as KCNE1.
• Polypharmacy increases the risk of interactions; the Beers Criteria list medications to avoid or use with caution.
• Genes such as CYP2C19, CYP2C9 and CYP2D6 interact with age, especially for women in the perimenopausal period.
• Regular medication reviews and pharmacogenetic testing can help make prescribing safer for seniors.

Frequently asked questions

Why do older people need lower doses of some medications?

With age, the liver and kidneys clear many drugs more slowly, and changes in body fat and water can raise drug levels. Older adults are also more sensitive to the effects of many medications.

Does drug absorption change with age?

Drugs may be absorbed more slowly, but the total amount absorbed usually changes little. Changes in distribution, liver metabolism and kidney clearance matter more.

Does menopause change how my medications work?

It can. Estrogen affects several drug-metabolizing enzymes, so falling estrogen levels at menopause, or starting or stopping hormone therapy, can change the levels of some medications, such as lamotrigine. Ask your pharmacist whether your medications need monitoring.

Which medications are riskiest for seniors?

Sleeping pills and benzodiazepines, opioids, blood thinners, anti-inflammatory painkillers, drugs with anticholinergic effects and medications cleared by the kidneys need extra care. The Beers Criteria provide a detailed list.

Why are seniors at higher risk of drug-induced heart rhythm problems?

Older adults often take several medications that prolong the QT interval, clear drugs more slowly and are more prone to dehydration and low potassium. Genetic variants in heart ion channel genes such as KCNE1 can increase the risk further.

Do genes still matter in older adults?

Yes. Genes such as CYP2C19, CYP2C9 and CYP2D6 continue to affect drug levels and response, and their effects can combine with age-related changes, especially in poor metabolizers.

Is it too late to get a pharmacogenetic test in older age?

No. Older adults often take the most medications, so a pharmacogenetic test can be especially useful, and the results apply to future prescriptions as well.

References

Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6-14.

2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.

Bosch EL, Sommer IEC, Touw DJ. The influence of female sex and estrogens on drug pharmacokinetics: what is the evidence? Expert Opin Drug Metab Toxicol. 2025;21(6):637-647.

Pennell PB. 2005 AES annual course: evidence used to treat women with epilepsy. Epilepsia. 2006;47 Suppl 1:46-53.

Kääb S, Crawford DC, Sinner MF, et al. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circ Cardiovasc Genet. 2012;5(1):91-99.

Lopez-Medina AI, Chahal CAA, Luzum JA. The genetics of drug-induced QT prolongation: evaluating the evidence for pharmacodynamic variants. Pharmacogenomics. 2022;23(9):543-557.

Ishizawa Y, Yasui-Furukori N, Takahata T, et al. The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics. Clin Pharmacokinet. 2005;44(11):1179-1189.

Brenner SS, Herrlinger C, Dilger K, et al. Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Clin Pharmacokinet. 2003;42(3):283-292.

Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther. 2020;108(2):191-200.

Miao L, Yang J, Huang C, Shen Z. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol. 2007;63(12):1135-1141.