Physiological Changes That Affect How Older People Metabolize Medications
A range of physiological changes that may affect drug metabolism occurs with age. The liver plays a central role in the termination of drug action and has, therefore, been well studied. Liver size or volume and hepatic blood flow both decrease with age, but these changes are not associated with changes in liver structure (Schmucker, 2001; Zeeh, 2001). Other physiological changes that occur with aging include reduced body mass and basal metabolic rate, reduced proportion of body water, increased proportion of body fat, decreased cardiac output, altered relative tissue perfusion, decreased plasma protein binding, reduced gastric acid production and gastric emptying time, and reduced gut motility and blood flow (see Table 1, Herrlinger and Klotz, 2001).
Although the effect of aging on human drug metabolism has been much studied, few generalizations about how aging affects human drug metabolism have emerged. Such studies are complicated by several factors, including the heterogeneity of the aged population, genetic polymorphisms24 of human drug-metabolizing enzymes, and the methodologies and selection of drugs used to quantify drug metabolism. The evaluation of in vivo human drug-metabolism is best expressed by the pharmacokinetic term clearance (Cl) and, more specifically, by the plasma clearance (Cl p) (Herrlinger and Klotz, 2001). Cl p is the virtual volume of plasma cleared of drug in a unit of time and is, therefore, related to the volume in which the drug is distributed (V d) and the rate at which it is eliminated (k el). Hence, Cl p = (V d )(k el ) and has the dimensions of (volume) (time) -1, i.e., mL min -1.
The interpretation of the clearance of a drug must also be tempered by several factors, including Phase-I versus Phase-II metabolism, activity of metabolizing enzymes, degree of hepatic extraction, extent of protein binding, hepatic blood flow, liver size or volume, and extent of extrahepatic drug metabolism (Brenner et al., 2003) . Given the range of variables that affect the interpretation of human drug metabolism, it is not surprising that the literature is inconsistent on whether aging significantly affects drug metabolism.
Drug-metabolism reactions have traditionally been described as Phase-I and Phase-II reactions. The liver plays a central role in both Phase-I and -II drug-metabolism reactions, but significant extrahepatic drug metabolism also occurs. (Indeed, significant drug-metabolizing capacity is present in the intestine; the inactivation of intestinal drug-metabolizing enzymes by grapefruit juice is the basis of the increased bioavailability of some drugs (Dahan and Altman, 2004)). Phase-I reactions are functionalization reactions that insert or unmask functional groups, e.g., a hydroxyl group. Cytochrome P450-catalyzed oxidative reactions are the most common Phase-I reactions, but other oxidative as well as reductive and hydrolytic reactions are also important for some drugs. Phase-II reactions enzymatically couple a drug or, more commonly, a drug metabolite produced by a Phase-I reaction with an endogenous acceptor molecule. Glucuronide formation is most common Phase-II reaction. Significantly, both Phase-I and -II drug metabolism reactions yield products that are usually less active pharmacologically and more polar and, therefore, readily excreted. Hence, Phase-I and -II drug-metabolism reactions play a major role in the duration and termination of drug action.
As indicated above, reactions catalyzed by the cytochromes P450 family of enzymes are highly important for human drug metabolism. There are more than 50 known genes (CYPs) that encode the human cytochromes P450s (CYPs),25 but approximately 15 CYPs are involved in drug and chemical metabolism and of these only six subfamilies (CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, and CYP3A) are important for human drug metabolism (Kinirons and O'Mahony, 2004) .
Some recent examples suffice to illustrate approaches taken to evaluate the role of the cytochromes P450 in human drug metabolism. Gorski, Vannaprasaht, Hamman, Ambrosius, Bruce, Haehner-Daniels, and Hall (2003) studied the effect of age, sex, and rifampin26 administration on intestinal and hepatic cytochromes P450 3A (CYP3A) activity with midazolam27 as the substrate. CYP3A catalyzes the metabolism of, say, 50 percent of clinically used drugs and is, therefore, of much importance. Rifampin is a well-known inducer of CYP3A, i.e., it produces a marked increase in the activity of CYP3A. The authors observed that there was no significant difference in the systemic clearance of midazolam between young (fourteen females: 26 ± 4 years; fourteen males: 27 ± 4 years) and elderly (fourteen females: 72 ± 5 years; ten males: 70 ± 4 years) subjects and between male and female subjects. Rifampin markedly increased the clearance of midazolam in both old female and male subjects, but marked interindividual variability in the extent of induction by rifampin was observed.
Brenner et al. (2003) studied the effect of age (twelve males aged 31.7 ± 5.0 and twelve males aged 68.3 ± 2.1 years) and CYP2C9 genotype on the steady-state disposition of diclofenac28 (a nonselective COX inhibitor) and celecoxib29 (a selective COX-2 inhibitor). No age effect on the clearance of either diclofenac or celecoxib was observed. The area-under-the-curve (AUC)30 for diclofenac was lower in the elderly subjects than in the younger subjects, but this was attributed to the higher bodyweight of the elderly subjects. Similarly, no association between CYP2C9 genotype and disposition of the study drug was observed.
Greenblatt et al. (2004) investigated the effect of age on the pharmacokinetics of triazolam, which is metabolized by CYP3A. The 61 male and female subjects were divided into three groups each: young males (29 ± 1.6 years), intermediate-aged males (47 ± 1.6 years), and elderly males (67 ± 1.5 years); young females (29 ± 1.6 years), intermediate-aged females (44 ± 1.9 years), and elderly females (68 ± 1.5 years). No difference in the clearance of triazolam was found among the groups of female subjects. In male subjects, however, no difference in the clearance of triazolam was found between the young and elderly groups, but, when age was evaluated as a continuous variable, the AUC increased with age and the clearance decreased with age, indicating increased bioavailability and decreased elimination of triazolam, which could lead to drug accumulation and adverse reactions.
Herrlinger and Klotz (2001), Schmucker (2001), and Kinirons and O’Mahony (2004) have reviewed the relationship between age and human drug metabolism. These authors conclude that although some measures of drug metabolism are diminished in the elderly, significant interindividual variability in drug metabolism, drug action, and adverse reactions characterizes the elderly population.
While few generalizations are possible in this area, the data presently available do not allow us to dismiss or disregard the potential effects of aging on drug metabolism.
24 Genetic polymorphisms are defined as variations (mutations) in DNA that are observed in 1 percent or more of the population. Variability in the level of expression or function of enzymes, responsible for metabolizing most prescription medications, can have a profound effect on drug efficacy. Some genetic polymorphisms lead to deficiency of these enzymes in some individuals, which can result in an increased risk of concentration-related toxicity. In other individuals polymorphisms enhance enzyme activity, resulting in lower drug concentration, and decreased response to therapy. For drugs such as codeine, which must be activated by enzymes in the body, an inherited deficiency in the activating enzyme can markedly reduce drug response (such is the case for 6% to 10% of Caucasians). Source: http://www.signaturegenetics.com/sgtiles/en/download/physician_nb_5684.pdf
26 Rifampin is used to treat certain bacterial infections. It is used with other medicines to treat tuberculosis. Rifampin is also taken by itself by patients who may carry meningitis bacteria in their noses and throats (without feeling sick) and may spread these bacteria to others.
28 Diclofenac is used to relieve the pain, tenderness, inflammation (swelling), and stiffness caused by osteoarthritis and rheumatoid arthritis and ankylosing spondylitis. It is in a class of medications called nonsteroidal anti-inflammatory medications (NSAIDs), and works by stopping the body's production of a substance that causes pain and inflammation.
29Celecoxib is used to relieve the pain, tenderness, inflammation (swelling), and stiffness caused by arthritis and to treat painful menstrual periods and pain from other causes. It is also used to reduce the number of polyps in the colon and rectum in patients with a disease called familial adenomatous polposis. Celecoxib is in a class of NSAIDs called COX-2 inhibitors that work by stopping the body's production of a substance that causes pain and inflammation. COX-2 inhibitors may cause less stomach bleeding and ulcers than similar medications.