Specialty Corner: Age-Related Pharmacokinetic Changes and the Impact on Statin Therapy in Older Patients

While there is evidence for atherosclerotic cardiovascular risk reduction with statins in both primary and secondary prevention in older patients, there is a higher incidence of associated muscle symptoms and discontinuation because of those symptoms.1-3 Thus, consideration of the risk-benefit ratio of statins in older patients is recommended.4

Conventionally, the phrase “older patients” has been defined most frequently as a chronological age of 65 years and older. Older patients often have several risk factors for statin-associated muscle symptoms, including polypharmacy, kidney and/or liver dysfunction, hypothyroidism, and vitamin D deficiency.5 Additionally, advanced age is a risk factor. This may be due, in part, to the fact that older patients are more likely to have other risk factors, but age-related physiologic changes also can influence the fundamental pharmacokinetic processes of absorption, distribution, metabolism, and excretion.6–8 These processes will be altered in different ways, depending on the patient; however, they ultimately can affect overall systemic exposure to statins and increase the risk for muscle and other adverse effects.

The aging process can affect several factors that are involved in the dissolution and absorption of oral dosage forms, including gastric emptying, gastrointestinal motility, gastric acidity, gastrointestinal blood flow, and intestinal surface area.8 Studies of medications changing gastrointestinal pH did not affect the bioavailability of pravastatin or atorvastatin but did increase systemic exposure of fluvastatin.9–11 No data are available evaluating other statins. Decreases in gastrointestinal motility would be expected to impact the poorly soluble statins, such as simvastatin, atorvastatin, and lovastatin, where increased transit time will allow longer time for dissolution and may result in increased total absorption. However, this would not be expected to have a significant clinical impact.8

Once dissolved, medications typically cross the intestinal mucosa, either by passive diffusion or by active carrier-mediated transport. The permeability of the mucosa to passively diffused medications does not appear to change with age; however, the active uptake of medications may be affected.8 Indeed, the active transport of several nutrients, including calcium and vitamin B12, do seem to be reduced in older adults.12,13 P-glycoprotein is a transmembrane transporter on the luminal surface of the intestine that functions to efflux drugs back into the lumen. The effect of aging on this transporter is still under active study; however, both increased and decreased activity have been observed.14 Most statins, except for rosuvastatin and fluvastatin, are substrates for P-glycoprotein and, thus, may be affected by alterations in its function.15

Some medications undergo metabolism prior to reaching systemic circulation, which is called first-pass metabolism. Most of this occurs in the liver; however, it also can occur in the intestine. Aging can reduce liver blood flow and mass, resulting in a reduction in first-pass metabolism.8 All statins, with the exception of pitavastatin, show high first-pass metabolism and subsequent low bioavailability.15 Small decreases in the amount of medication extracted by the liver can have significant changes in statins’ serum concentrations.16 Simvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin would be expected to be the most significantly impacted by reductions in first-pass metabolism, because they have the lowest bioavailabilities.15,17

Following absorption, the amount of pharmacologically active drug is dependent on its tissue distribution and extent of protein binding. This is referred to as its volume of distribution. There is a significant change in both body composition and plasma protein concentration, which may affect this pharmacokinetic process.8 With aging, there is a reduction in total body water and muscle mass and an increase in body fat.18,19 The volume of distribution of the water-soluble statins, pravastatin, and rosuvastatin, therefore is likely to be reduced and the same administered dose will result in increased peak-serum concentrations. The lipid-soluble statins — simvastatin, lovastatin, atorvastatin, fluvastatin, and pitavastatin — will have an increased volume of distribution and will take longer to be cleared from the body.8 A reduction in plasma albumin concentration of around 10 to 15 percent has been observed in older adults.20 All statins except pravastatin are highly bound to albumin; therefore, theoretically, older individuals will have a higher percentage of unbound (free) drug available to exert both therapeutic and adverse effects.15 In practice, changes in protein binding are unlikely to result in clinically significant effects because free drug is more readily cleared; however, coexisting liver or kidney dysfunction could certainly overcome this and result in a higher likelihood of toxicity.

Metabolism is an important step for drugs that require conversion to a more soluble form to be excreted by the kidneys. Metabolism occurs via cytochrome P450-mediated reactions (oxidation, reduction, and hydrolysis) and conjugation (glucuronidation, acetylation, and sulfation). These processes are categorized as Phase I and Phase II metabolism, respectively. While metabolism can take place in the intestine (discussed earlier) and the kidneys, the liver is the major site for this pharmacokinetic process. Hepatic metabolism depends on several variables, including rate of drug supplied to the liver by the blood, the transfer of drug from the blood to the hepatocyte, and the capacity of the hepatocyte to metabolize the drug.21

As previously mentioned, the blood flow to the liver is reduced with age. There also is a decrease in liver size.17,22 The degree to which this will affect drug metabolism depends on the drug’s hepatic extraction ratio, which is defined as the ratio of hepatic clearance of a drug in relation to hepatic blood flow. Drugs that have a high extraction ratio will be more affected by reduced blood flow than low-extraction drugs.17,23 All statins mainly are cleared by the liver. Simvastatin, lovastatin, atorvastatin, and fluvastatin all have extraction ratios of more than 70 percent, which is considered to be high. Pravastatin and rosuvastatin have ratios of 45 and 63 percent, respectively, which is classified as intermediate.15

After reaching the liver, drugs must cross the sinusoidal endothelium and travel through the space of Disse before it enters the hepatocyte. Age-related changes in the liver’s sinusoidal endothelium that may impede drug transfer have been observed.24 However, while statins do passively diffuse across cell membranes; they also are actively transported into hepatocytes by uptake transporters, among which are the organic anion-transporting polypeptides (OATPs). The most wellknown and most important of these is OATP1B1, but others involved in statin transport include OATP1B3, OATP2B1, and OATP1A2.15 In animal studies, aging has been associated with decreased mRNA expression of OATPs; however, it remains to be determined how this translates to humans and the degree to which it would affect hepatic statin uptake.25

Clearance of drugs undergoing Phase I metabolism (CYP P450-mediated) has been shown to be reduced by 30 to 50 percent in older adults.22 This is more of an effect of reduced hepatic blood flow and liver size than changes in the expression of the cytochrome P450 (CYP) enzymes.8 Additionally, the availability within the hepatocyte is reduced because of agerelated pseudocapillarization. This limits CYP-catalyzed reactions, which are highly dependent on oxygen as a co-substrate.26 Lovastatin, simvastatin, fluvastatin, and atorvastatin undergo significant metabolism by CYP P450 enzymes and, therefore, are likely to be affected by these changes.15 Older adults are more likely to take multiple medications, thus increasing the potential for both inhibition and induction of Phase I metabolism. Fortunately, most studies have indicated that these drug-interaction processes are not affected by aging.

Phase II metabolism does not appear to be altered with older age; however, in frail older adults, it may be reduced.8,22 Still, this would not be expected to have a significant effect on the metabolism of statins, because glucuronidation has only a minor impact on total statin clearance.15

Elimination of drugs that do not undergo significant liver metabolism, occurs through the kidneys. There does appear to be a decrease in renal function with age; however, accurate prediction is difficult because of comorbidities and medications that also negatively affect the glomerular filtration rate (GFR).8

More than two-thirds of older adults have hypertension, and more than one-quarter have diabetes.27,28 More than one-third of adults in the U.S. have Stage III or IV chronic kidney disease.29 Many also take nephrotoxic medications, including nonsteroidal anti-inflammatory drugs, ACE inhibitors, angiotensin receptor blockers, and corticosteroids. Therefore, it can be assumed that the average population of older adults will have reduced kidney function. The only statins that undergo significant renal elimination are pravastatin and rosuvastatin. All other statins primarily are eliminated in the feces via bile after being metabolized in the liver.15 This occurs via P-glycoprotein, which, as discussed earlier, is currently under study as to the effects of aging.

It is also important for the clinician to differentiate the “fit” older patient from the “frail” older patient. The frail older patient represents a subgroup that will have other variables impacting the effect of medications besides pharmacokinetic changes. These variables include comorbid medical conditions, nutritional status, and organ function.

In summary, any age-related change in physiology can potentially affect the disposition of drugs. The most clinically significant changes pertaining to statins are those affecting liver extraction, metabolism, and excretion, given that is their primary pharmacokinetic pathway. The potential impact of these changes should be a consideration in the riskbenefit discussion of statin therapy when presented with a patient over the age of 65, especially if the patient has multiple comorbidities and poor health status.

Disclosure statement: Dr. Stewart has no disclosures to
report.