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Exercise Is Medicine, But Does It Interfere With Medicine?

McLaughlin, Mackenzie; Jacobs, Ira

Exercise and Sport Sciences Reviews: July 2017 - Volume 45 - Issue 3 - p 127–135
doi: 10.1249/JES.0000000000000111
Perspectives for Progress
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Exercise frequently is prescribed therapeutically, either on its own or combined with drugs. A drug’s absorption, distribution, metabolism, and excretion can be affected by the user’s anatomy and physiology, which are both changed by the myriad of complex adaptations to acute and chronic exercise. This article reviews the research that suggests exercise may influence a drug’s plasma concentration, and thus its efficacy and safety.

Exercise elicits anatomical and physiological adaptations and, therefore, has the potential to influence drug pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion).

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, Ontario, Canada

Address for correspondence: Ira Jacobs, Faculty of Kinesiology & Physical Education, University of Toronto, 55 Harbord St, Toronto, Ontario, Canada M5S 2W6 (E-mail: ira.jacobs@utoronto.ca).

Accepted for publication: February 3, 2017.

Editor: Barry Braun, Ph.D., FACSM.

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Key Points

  • Exercise increasingly is prescribed to treat many diseases and disabilities, although a trend for increased use of drugs also exists. Yet, interactions between drugs and exercise rarely are investigated.
  • Exercise is associated with physiological and anatomical changes grossly affecting virtually every organ and tissue and, therefore, may influence a drug’s pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion).
  • The transient responses to acute exercise, such as the diversion of blood away from the liver, reduced plasma volume, and blunted drug-metabolizing enzyme activity, are suspected to quickly and profoundly alter a drug’s blood concentration.
  • Chronic adaptations to exercise include body recomposition, a more resilient gastrointestinal tract, greater bile acid production, and enhanced enzyme activity — which, when taken together, have the potential to elicit significant changes in drug pharmacokinetics.
  • A drug’s dosage may need to be personalized for athletic individuals to ensure plasma drug concentrations remain effective and nontoxic.
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INTRODUCTION

Pharmacology is composed of two branches: pharmacodynamics (PD) and pharmacokinetics (PK). Like many exercise physiologists, we have been intrigued with the former, i.e., the study of drug effects on the body, specifically, the ergogenic PD effects of drugs on exercise performance (28,29). Recently, however, our focus has shifted to the mechanisms by which exercise modulates drug PK (i.e., absorption, distribution, metabolism, and excretion; ADME) in the exercising individual (Fig. 1). Relatively few drugs have been studied for a possible interaction with exercise (16,30,62) yet the area of exercise pharmacokinetics (EXS-PK) has been previously reviewed (33,39,56), the most recent publication being in 2011 (38). The purpose of this current perspective for progress is to review and expand on past EXS-PK concepts, explain potential new drug-exercise interactions that have yet to be considered, and foster a call to action for more research relating to EXS-PK.

Figure 1

Figure 1

This topic remains relevant because public awareness of the health benefits of exercise is at an all-time “high,” as is the tendency of physicians to prescribe exercise in accordance with the notion that “exercise is medicine.” The Exercise is Medicine® initiative of the American College of Sports Medicine and the American Medical Association is but one of myriad examples of the translation of research from the exercise science community into public health initiatives. In addition, prescription drug use is common. The Center for Disease Control’s National Center for Health Statistics reported that for the years 2009–2012, approximately 50% of all Americans reported ingesting one or more prescription medications in the previous month, and 10% ingested five or more drugs (50). Thus, exercise may be prescribed as part of a therapeutic regimen for patients that also includes the use of medication. For example, exercise usually is recommended to treat clinical depression and anxiety with the simultaneous use of antidepressants (3). In general, drug regulatory authorities, such as the U.S. Food and Drug Administration, do not require information about EXS-PK interactions to be included within the clinical trial data that are used to assess drug safety and efficacy.

In light of the accelerating trends mentioned previously and neglect by the pharmaceutical industry to examine such interactions, this review will provide a current perspective about EXS-PK and, by doing so, contribute to what we hope will develop into another accelerating trend — i.e., increased attention from the exercise science community to studying the potential for exercise to affect important PK mediators encompassed within ADME.

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PHARMACOKINETICS

PK typically is represented by a drug’s maximum plasma drug concentration (Cmax), the time at which Cmax occurs postingestion (Tmax), the time delay before first-order absorption kinetics commence (lag time; tlag), the time taken for plasma drug concentration to decrease one half (half-life; t1/2), and the fraction of a dose that is absorbed at the site of administration and enters the circulation in its native form (bioavailability; F). Figure 2 is a schematic depiction of these variables. Only the fraction of drug that is unbound (fu) can elicit a PD effect. The fraction and strength (i.e., affinity) of attraction to plasma proteins (PP; e.g., albumin, alpha-1 acid glycoprotein (α1-AGP), sex hormone–binding globulin (SHBG), and lipoproteins) (17) create competition for the drug between PP and receptors or enzymes. Binding to PP impedes the drug’s effect on receptors or the extent of metabolism by CYP450 drug-metabolizing enzymes (DMEs). Thus, area under the plasma drug concentration-time curve (AUC) shows the total amount of drug available systemically, but only fu can elicit a response.

Figure 2

Figure 2

Anatomical and physiological attributes of a person govern the processes that mediate a drug’s ADME. The Table lists selected physiological changes during acute exercise and the associated PK parameters with the potential to be significantly affected.

TABLE

TABLE

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ABSORPTION

Drug absorption is the movement of the drug molecule from the site of administration to the bloodstream (the primary circulatory compartment) where it is then distributed throughout the tissues. The physicochemical properties of the drug (e.g., lipophilicity, partition coefficient, and pKa), blood flow to the site of administration, and surface area of absorption determine the extent of absorption. The passive diffusion of a drug across a biological barrier (e.g., intestinal mucosal, alveolar epithelium, or cutaneous tissue) is dictated by Fick’s law (equation 1):

where dQ/dt is the rate of diffusion, D is the diffusion coefficient, A represents surface area of the membrane, K is the lipid-water partition coefficient of the drug, h is membrane thickness, and C1C2 is the difference in drug concentration of the original medium (C1) and the medium which the drug is diffusing into (C2) (72). An increase in temperature increases Brownian motion of the drug molecules — elevating the rate of diffusion — and a greater blood flow to the absorbing tissue increases the rate of drug removal from the internal tissue at the site of entry, increasing the gradient and flux between epidermal/epithelial and endothelial media (72).

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Gastrointestinal Absorption

Peroral drug absorption relies on active transport and passive diffusion across the gut epithelium. The small intestine (SI) is the major site for absorption for most drugs because of its large surface area from villi and microvilli and extensive vasculature, and the transit time through it is controlled by the rate of gastric emptying (GE) and gastrointestinal (GI) motility (11). Passive diffusion favors the diffusion of small, lipid-soluble (unionized), low polarity molecules from the GI tract through the mucosal tissue to the supplying vasculature and is represented by equation 1. Drugs that cannot traverse the epithelium undergo carrier-mediated transmembrane transport via proteins that facilitate absorption of natural substrates. This transporter-mediated flux is governed by Michaelis-Menten kinetics and can be represented by equation 2 (84). A represents the amount (i.e., mass) of drug absorbed, Amax is the theoretical maximum of A, D is the dose, and Km is the Michaelis constant, which represents the mass of drug at which the rate of transport is half saturated. At the time of this writing, no reports were found about changes in intestinal drug transport proteins in response to exercise.

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Gastric Emptying

GE, or the rate of drug being supplied to the SI, has implications on rate and extent of absorption. GE generally decreases for solid food and hyperosmotic drinks (49) during exercise at or above 70% maximal aerobic workload (Wmax) (6,60), at a rate proportional to increasing exercise intensity (37). A slower GE would delay drug introduction into the SI, increasing tlag, extending drug absorption over time, and potentially flattening the AUC. The longer mucosal drug residency time extends the time that gastric and intestinal juices, and intestinal DMEs and transporters, interact with the drug, resulting in increased breakdown, solubilization, metabolism, and transporter influx/efflux (Table) (54). These effects would be less pronounced in endurance-trained athletes because their basal GE rates are faster than nonathletes (7), which is likely a training adaption.

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Gastrointestinal Motility

A review by Casey et al. (9) outlines that exercise results in an increase in catecholamines and the GI hormonal peptides motilin, secretin, gastrin, peptide histidine-methionine, and vasoactive intestinal peptide, all of which are known to decrease motility and increase transit time during intense aerobic exercise. β-Endorphin, an endogenous opioid, also increases during high-intensity exercise (>75% V˙O2max) and is associated with cessation of high intestinal motility observed postprandial (76). This interaction is intensity dependent (76); thus, untrained individuals likely experience more consistent intestinal motility interruptions at the same absolute intensity than a more aerobically trained individual.

Research on the PK of drugs coadministered with GI-influencing drugs (22) suggests that a decreased GI motility during aerobic exercise likely would affect orally ingested drugs. Inhibiting motility with the anticholinergic, propantheline, increased Tmax of atenolol by 2 h and bioavailability by 36%, which was attributed to a greater dissolution from a prolonged retention time in the stomach (59). In contrast, administration of 0.05 mg·kg−1 of IV morphine (an exogenous opioid that also inhibits motility) impacted acetaminophen absorption such that Tmax also increased (from 90.3 min to 129.0 min); however, the AUC(0–95) decreased by 44% (90). Because the timing of exercise and drug ingestion is variable, an increased tlag (Fig. 2) could be expected from prolonged GE when drug ingestion is close to the start of exercise. Cmax and AUC would be altered in a manner dependent on the drug’s physicochemical properties and its formulation.

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Transit Time

Passage through the SI during exercise (i.e., transit time) is typically faster for solid foods during low-intensity exercise but delayed during high-intensity exercise (9). A 6-wk aerobic training program was reported to shorten resting transit time by 22.8% (11).

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Gastrointestinal pH

Because the GI tract partitions the luminal contents from the circulatory compartment, changes in pH of the gastric lumen and the supplying vasculature can affect a drug’s degree of ionization, affecting its absorption. Equation 3 (acidic drugs) and equation 4 (basic drugs) show when the unionized form predominates with respect to a drug’s pKa and the pH of the medium.

The pH partition hypothesis states that a drug will accumulate in the compartment in which it is more ionized because only the unionized molecule can cross biological barriers. This is known as ion trapping. With changes in pH on either side of the GI mucosal membrane, drug ionization, and thus absorption, can change.

During exercise, decreases in luminal gastric pH are blunted because gastric acid secretion, basal acid output, and concentrations of HCl are significantly lower (41). Van Nieuwenhoven et al. (80) confirmed a blunted gastric acidification (pH = 3.6 during exercise vs pH = 2.7 at rest) in participants who cycled at 70% Wmax for 90 min after ingestion of a carbohydrate-electrolyte beverage. Across the mucosal membrane (opposite the lumen) in the circulation, capillary blood pH measured from a finger prick was shown to decrease, on average, from a pH of 7.42 to 6.94 after five repeated bouts of maximal running (25). Narrowing of the difference between plasma pH and GI luminal pH affects absorption of acidic and basic drugs. For a weakly basic drug, the relatively more alkaline GI environment during exercise will cause a greater drug proportion to be unionized and able to traverse the gut mucosa into the vasculature. When the drug enters blood that is more acidic because of exercise, it will become ionized and trapped in the circulatory compartment. A weakly acidic drug will have opposite ionization states in this scenario and may experience a more limited absorption. Thus, it is possible that absorption of weakly basic drugs is augmented, and absorption of weakly acidic drugs is hindered, during exercise.

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Intestinal Permeability

Passive and active SI absorptions also are affected by exercise. Intestinal acidosis from tissue hypoxia results in a decreased transcellular permeability and an increased paracellular permeability. Active, carrier-mediated diffusion of 3-O-D-methyl M-glucose was decreased during cycling at 70% Wmax for 90 min (80), which is likely a result of hypoxic mucosal injury from intestinal hypoperfusion (9). In contrast, passive, paracellular permeability is implicated during aerobic exercise, allowing a greater absorption. Treadmill running at 80% V˙O2max (but not 60% V˙O2max) increased passive intestinal permeability of lactulose, a polysaccharide, 30 min into the 1 h protocol (53). This likely results from damage to the tight junctions between SI epithelial cells, increasing the intercellular space (66).

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Absorption Conclusion

Based on the aforementioned, it is tempting to speculate that exercise results in a slower GE, a more relaxed SI motility, a longer transit time, and blunted absorption of weakly acidic and transcellularly absorbed drugs. However, a generalizable model of the expected influence of exercise on drug absorption is, so far, precluded due to many factors, including the physicochemical (e.g., acidity/basicity, pKa, and size) and biochemical (e.g., transcellular vs paracellular transport) drug properties and anatomical/physiological interindividual variations (e.g., GI drug transporter proteins, hormone response, and training status) that would require many experiments with different drug-exercise timing combinations. Anecdotally, levodopa users who engaged in trials to assess their individual drug and exercise timing interactions planned their exercise after drug ingestion to enhance its absorption or ingested a larger dose if they had just exercised (8). It was confirmed that the perceived efficacy of levodopa was in line with measured plasma samples, which showed varying absorption characteristics, being delayed in five patients, increased in three, and unchanged in two (8).

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DISTRIBUTION

The apparent volume of distribution (Vd) of a drug describes the theoretical volume into which a drug is distributed/dissolved into, assuming all tissues are homogeneous. It is determined by the volume of water in the plasma (Vp), volume of water in tissues (VT), and the unbound fraction in plasma (fu) and tissue (fuT), as shown in equation 5:

A drug’s plasma concentration is used as an indirect measure of its concentration at the drug’s receptor site. Shifts in Vd influence a drug’s plasma concentration and, thus, the necessary dose to achieve the desired effect. Therefore, changes in the Vp and VT, and the fraction of drug bound to PP versus tissue proteins, determine the drug’s Vd. A large Vd means the drug binds more favorably to tissue compared with PP, whereas a small Vd suggests the opposite.

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Tissue Versus PP Binding

Exercise may affect a drug’s Vd by modulating the variables in equation 5. An increase in mass of drug-binding tissue (e.g., skeletal muscle) (31,89) increases VT, and thus Vd. An increase in the molar concentration of the PP (e.g., albumin, α1-AGP, SHBG, and lipoproteins) involved in binding is associated with an increase in the maximal binding capacity, which decreases fu (79), and thus the fu/fuT ratio, shrinking the Vd and increasing total drug in the circulatory compartment. As a result, we speculate that highly PP-bound drugs, such as warfarin (99% bound), likely would experience a decreased fu (79,81) and Vp, and, thus, Vd from the hemoconcentrated state experienced by athletes when they become hypohydrated during exercise (67). For example, a 12% decrease in plasma volume (PV) and a 14% increase in PP have been reported in male runners after a 60-min run (64). A modest change in fu of highly bound drugs may seem insignificant, but the magnitude of change is rather large. Consider the case of warfarin; a change in fu from 1% to 0.1% equates to a 10-fold decrease in its unbound fraction.

Tissue perfusion during exercise increases in most organs except for the splanchnic vasculature, which comprises the liver and kidneys (Fig. 3). The redistribution of blood during exercise may affect tissue-drug interactions because increased perfusion of tissues can result in increased absorption from the epidermal/epithelial site of administration or increased accumulation in internal tissues, such as the muscle, liver, and brain. For example, digoxin affinity for membrane-bound Na+-K+-ATPase in the skeletal muscle is responsible for the observed 29% increase in skeletal muscle concentration and 39% decrease in serum concentration in subjects after 60 min of cycle ergometry at a moderate intensity (heart rate (HR) = 140 beats·min−1) (31).

Figure 3

Figure 3

Chronic training is associated with an increase in fat-free mass (FFM) that is well-hydrated and a proportional decrease in adipose tissue, which is less hydrated and poorly perfused. This corresponds with an increase in VT, and thus Vd. A comparison of individuals with differing FFM percentage and total body water revealed that the Vd of alcohol, which dissolves well in hydrated tissues, was indeed higher in leaner individuals (12). In addition, endurance training results in an expanded PV (64), which equates to a larger Vp, and thus Vd.

Drug acidity can influence drug binding to tissues. Compared with acidic drugs, basic drugs have been reported to bind more readily to muscle tissue (35) and α1-AGP, whereas acidic drugs bind to albumin (5). Exercise is listed as a mediator of increased albumin concentration (51), suggesting that weakly acidic drugs experience a decreased fu during physical activity.

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Blood pH and Temperature

An increase in blood lactate from intense exercise can be associated with a decrease in blood pH from 7.4 to as low as 6.8 during exhaustive exercise (42). A review by Hinderling and Hartmann (26) reported that all of the 30+ basic drugs investigated experienced a greater fu with decreasing blood pH, whereas the acidic drugs experienced inconsistent fu changes at a lower pH. Increased fu occurs from a conformation change in albumin during a pH decrease from 9 to 6 (83) and a decrease in the high-affinity binding forms (ionized for acidic and unionized for basic drugs) that bind to albumin (acidic drugs only), α1-AGP, and lipoproteins (26).

Changes in temperature also have been shown to increase fu. An approximately 1°C rise in serum temperature corresponded to a 0.27% increase in the free fraction of propranolol (55), a weakly basic drug. Cycling for 30 min at 70% V˙O2peak has proved sufficient to raise core body temperature by approximately 1°C (48).

Therefore, an increase in blood acidity, and perhaps temperature, may increase fu, potentially facilitating a greater PD effect.

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METABOLISM

Drugs are metabolized into more polar entities by CYP450 enzymes and then subsequently excreted in the urine and bile. CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 are the major DME because they are responsible for the metabolism of 85% of clinically used medications (91). Hepatic clearance (CLh; equation 6) represents the volume of blood filtered and stripped of drug by the liver per unit time. It is the combined efforts of hepatic metabolism and biliary excretion and is expressed in mL·min−1·kg−1:

Extraction ratio (ER; equation 7) is the ratio of drug metabolized when filtered by the liver and represents the efficiency of enzymes involved. ER is determined by the extent of drug binding to PP, hepatic blood flow (Qh), and the enzymes’ intrinsic clearance (CLint), which is the inherent ability of DME to metabolize a drug without the limitations of liver blood flow and protein binding. Qh can change within minutes from blood diversion during exercise, whereas CLint changes over hours to days because of the kinetics of enzyme inhibition and upregulation/downregulation by endogenous and exogenous mediators (86). The impact of enzyme activity can change rapidly when it is inhibited through competitive binding, whereas observed differences from enzyme upregulation/downregulation take longer (12 h to days) (2) to manifest because de novo synthesis of enzymes must occur (86). Cytokines can alter the rate of drug metabolism by inhibition (45), upregulation (in rats) (69), and, most commonly, downregulation of CYP450 DME messenger RNA (mRNA) synthesis (91).

These parameters are the basis for the characterization of drug metabolism into flow-limited and capacity-limited metabolism. When a greater proportion of drug undergoes metabolism (i.e., ER > 70%), the rate of CLh is dependent on the rate of blood flow to the liver and is termed “flow-limited.” In contrast, a “capacity-limited” drug is that which demonstrates metabolism of a lower proportion (i.e., ER < 30%) and is sensitive to changes in binding when the drug is highly bound (e.g., fu < 10%), making the extent of metabolism dependent on the relative affinity between PP and DME (70).

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Hepatic Blood Flow — The Acute Response

Interest in EXS-PK was stimulated by the demonstration of Rowell et al. (65) that aerobic exercise decreased clearance of indocyanine green dye (a marker of Qh because it is exclusively cleared by hepatic metabolism) to as low as 19% of resting values. At the onset of exercise, blood is shunted from the liver — an organ requiring only a quarter of the oxygen it is supplied with (65) and capable of increasing O2 extraction at a reduced flow rate (73) — to the working skeletal muscles in need of oxygen. Cycling for 1 h at 70% V˙O2max was associated with a drastic fourfold decrease in portal vein blood flow (0.63 L·min−1 to 0.14 L·min−1) (61). This reduced Qh translates to a reduction in clearance. Flow-limited drugs with a short t1/2 and small Vd likely are to be affected by such interactions, such as lidocaine (t1/2 = 90 min) (78) and recombinant tissue factor pathway inhibitor (t1/2 = 80 min) (32).

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Inflammation and Enzyme Activity — The Subacute Response

The inflammatory effects of exercise may influence drug metabolism. A review by Zanger and Schwab (91) showed that nearly all enzymes involved in drug metabolism are affected by inflammation, the typical response being downregulation of mRNA synthesis. Cytokines, the inflammatory mediators of the immune system, manifest these changes through transcription regulation of CYP450 genes (1,86,91). Exercise is associated with elevated levels of several cytokines in plasma, with IL-6 demonstrating the greatest increase in the circulation (77). IL-6 is termed a myokine because it is released from contracting skeletal muscle and its plasma levels are influenced by intensity, mode, and duration of exercise, the mass of muscle recruited during exercise, and the aerobic fitness of the individual, with higher exercise intensity correlating with increased plasma concentration (18). Moreover mRNA expression of hepatic DME (CYP2C8, 2C18, 3A4, 2C9, 2C19, and 2B6) is downregulated when incubated with cytokines in vitro, with IL-6 being one of them (1). Since those DMEs are involved in the metabolism of most of the prescription drugs, it is possible that there are inflammation-mediated effects of exercise on PK. This is a subacute response because cytokine-mediated enzyme downregulation takes hours to days to transpire (74).

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Training and Enzyme Activity — The Chronic Response

In contrast, chronic exercise is associated with a greater clearance via endogenous enzyme induction/upregulation. More aerobically fit mice had shorter sleeping times when sedated by hexobarbital, presumably because of increased CYP450 content and activity (19,20). Administration of the exogenous chemical inducers, noradrostenolone and spironolactone, had no additive effect on enzyme induction (20), suggesting a shared mechanism between endogenous and exogenous induction.

In humans, 3 months of daily physical activity (4–8 h) resulted in increases of 12% and 13% in the clearance of antipyrine (AP) and aminopyrine, respectively (4). The extent of AP clearance was modestly correlated with the increase in V˙O2max percentage of the subjects (4). Sprint and long-distance athletes also showed similarly enhanced AP metabolism compared with controls; there was no difference on enzyme induction between anaerobic and aerobic training (52). Different modes of exercise training, however, have resulted in inconsistent findings. A comparison between treadmill running and swimming in rats by Day et al. (14) revealed that the runners exhibited a 33%–35% decrease in CYP450 microsomal content, whereas the swimmers displayed a 27% increase in CYP450 content. This could result from a greater inflammatory response during running or a greater serum adrenocorticotrophic and corticosterone concentrations observed during swimming compared with intensity-matched running (10). These biomarkers are members of a network of stress hormones known to affect CYP450 DME (34).

The general increase in xenobiotic metabolism may result from an increased liver size and CYP450 content. Football players engaged in 1 yr of resistance training had a 13% increase in liver mass (44), and 6 wk of endurance training produced a 14% increase in liver weight and greater microsomal protein concentration (88). Although only speculative at this stage, a greater liver weight, and thus total enzyme concentration, could translate to a greater xenobiotic clearance.

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EXCRETION

Drugs are removed from the body primarily through urination with small contributions from expired air, sweat, breast milk, mucus, and bile. Polar, water-soluble, ionized, and sometimes conjugated metabolites are trapped in the primary circulatory compartment and filtered by the kidneys. Drugs of higher mass and typically lipid soluble are actively transported into the bile and secreted into the SI for excretion in the feces.

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Renal Excretion

Renal excretion of drugs is the combined effect of glomerular filtration rate (GFR), tubular secretion, and tubular reabsorption. Renal clearance is calculated by equation 8:

where Qu is the urine flow rate, Cu is the urine drug concentration, and Cp is plasma drug concentration (71). CO percentage to the kidneys during exercise decreases linearly with increasing exercise intensity (HR; r = −0.89) (23) to as low as 1% CO (Fig. 3). GFR is typically well maintained (85) yet reductions have resulted from endurance (40) and high-intensity runs of 1500 m and up (58). A reduced GFR will decrease Qu, and possibly CLr.

Changes in urinary pH do affect the degree of ionization of weakly acidic and weakly basic compounds, which could affect their excretion (21). Equation 3 shows an increased urinary pH will neutralize a weak base, causing a greater proportion to undergo passive tubular reabsorption, limiting excretion. A greater fraction of weak acids (equation 2) becomes ionized, decreasing reabsorption and increasing excretion. The alkalization of urine 180 min after the cessation of aerobic (pH = 6.2 to pH = 7.0) (47) and resistance exercise (pH = 5.98 +/− 0.21 to pH = 6.74 +/− 0.17) (46) potentially could affect excretion and reabsorption of drugs in the proximal and distal convoluted tubule, similar to the GI tract. Urine alkalization during exercise (45) results from a return in ventilation to preexercise values yet continued metabolism of blood lactate, leading to accumulation of CO2 and conversion to bicarbonate, which rapidly is excreted in the urine approximately 30 min after exercise cessation.

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Biliary Excretion

Compared with renal excretion, biliary excretion eliminates larger molecules that often are conjugated during metabolism. Biliary production and intestinal secretion increase, whereas intestinal reabsorption decreases from aerobic activity. Cycling at a mild intensity (200 kpm·min−1) for 30 min significantly increased bile acid excretion into the duodenum from 242 ± 74 μmol to 2204 ± 913 μmol (P < 0.05) (75). A longer duration study in mice showed that 6 wk of voluntary wheel running increased both total and relative (to liver weight) basal bile acid flow and bile acid excretion (87). In a similar study, exercise increased the excretion of acetaminophen, rose bengal, and reduced glutathione (82). Increased biliary production is believed to be a product of increased cholesterol turnover and decreased intestinal reabsorption (43). Meissner et al. (43) showed that mice running freely for 2 wk had greater bile acid secretion yet lower expression of transporters that facilitate bile acid absorption in the ileum. Therefore, it is reasonable to conclude that exercise results in an increase in biliary drug excretion.

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Future Perspectives

This review highlights the physiological changes to acute and chronic exercise that have, in our opinion, a well-founded potential for a direct effect on drug PK (Table). This review provides an update of the most influential EXS-PK interactions and introduces the topics of subacute and chronic exercise adaptations that also could affect PK. The magnitude of the exercise-induced changes in many of these variables is extreme compared with the changes observed in disease or injury states that many drugs are prescribed to treat, which makes it all the more surprising that EXS-PK interactions have received such limited attention.

As we encourage exercise in more at-risk and special populations that also are ingesting drugs regularly (e.g., cancer patients, psychiatric patients), the rationale for appropriately titrated drug doses becomes all the more important, particularly for drugs with narrow therapeutic windows. Moreover, the extreme physiological perturbations to acute exercise typically experienced on a regular basis by athletes pose lots of questions about drug efficacy and safety for this population as well. This brief review should motivate others to explore EXS-PK interactions with a view to clarifying and improving drug efficacy and safety.

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Keywords:

exercise physiology; exercise inflammation; exercise pharmacokinetics; CYP450 enzymes; personalized medicine; enzyme upregulation/downregulation; drug interactions

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