TY - JOUR
AU - Cohen,, Andrew
AB - Abstract Purpose Pharmacokinetic considerations in patients who have undergone Roux-en-Y gastric bypass (RYGB) are explored. Summary The prevalence of obesity, especially morbid obesity, has dramatically increased in recent years. In response, the number of bariatric surgeries performed has risen sharply, as this surgery is the technique demonstrated as being the most effective for sustained treatment of morbid obesity. RYGB, the most popular technique in the United States, combines the principle of restriction (dramatically decreasing stomach size) with malabsorption (bypassing the entire duodenum). It stands to reason that a decrease in gastric and intestinal absorptive surface area may considerably affect oral bioavailability of some drugs. Drugs that require a more acidic environment for absorption, uncoating, or activation and drugs that rely on intestinal transporters located in the duodenum for proper absorption would be most affected. Practitioners looking for guidance in tailoring pharmacotherapy to the RYGB patient will find little help in the primary literature at this time. Until more pharmacokinetic studies are available, practitioners may apply and log P of individual the principles of pKa drugs in the attempt to predict the potential impact of the RYGB on a drug’s absorption. Likewise, if a drug relies on certain transporters located with highest frequency in the duodenum, alternative therapies can be selected that do not rely on such transport mechanisms for absorption. Conclusion The pKa, log P, and intestinal transport mechanisms should be considered when determining which drugs may have altered pharmacokinetics in patients who have undergone RYGB. Absorption, Drugs, Drugs, availability, Obesity, Pharmacokinetics, Surgery With roughly one third of the U.S. population meeting the National Institutes of Health (NIH) definition of obesity (body mass index [BMI] of ≥30 kg/m2) and nearly six million of those meeting the criteria for morbid obesity (BMI of ≥40 kg/m2), obesity is becoming a national epidemic.1 The strain this disease has placed on health care systems has dramatically increased the number of both patients pursuing and health care providers recommending bariatric surgery. According to the NIH criteria, any patient with a BMI of ≥40 kg/m2 or a BMI of 35–39 kg/m2 with obesity-related comorbidities qualifies for bariatric surgery.1 Bariatric surgery is the approach proven to yield the most dramatic and sustainable reduction in weight and comorbid medical conditions.2,3 More than 200,000 bariatric surgeries are performed annually in the United States, and bariatric surgery is among the fastest growing areas of surgical practice today.4,5 There are four main types of bariatric surgery: (1) restrictive (gastric banding, gastroplasty), (2) restrictive with limited digestive capacity (sleeve gastrectomy), (3) malabsorptive (biliopancreatic diversion [BPD], jejunoileal bypass [JIB]), and (4) combination restrictive– malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion with duodenal switch)4,5 The purely malabsorptive procedures produce the greatest and most rapid weight loss but are also associated with more severe complications, the most concerning of which are major nutrient and vitamin deficiencies, presumably caused by the extensive bypassing of functional small intestine.5 For this reason, purely malabsorptive procedures have fallen out of favor, and RYGB has become the gold-standard surgical weight-loss technique. In RYGB, the surgeon staples off a new proximal gastric pouch that holds 15–50 mL. An incision is made 30–75 cm distal to the ligament of Trietz, and the Roux limb of the proximal jejunum is connected to the stomach pouch via a gastrojejunal anastomosis, bypassing the entire duodenum. The remaining portion of the proximal jejunum is reconnected via a jejunojejunal anastomosis to facilitate the passage of bile salts and pancreatic enzymes so they can mix with ingested food and drugs (Figure 1). In contrast to BPD and JIB in which the entire duodenum and jejunum are effectively bypassed, patients who undergo RYGB lose only 100–200 cm of proximal small bowel absorptive length, leaving roughly 4–5 m of functional small intestine. Figure 1 Open in new tabDownload slide Rearranged digestive tract after Roux-en-Y gastric bypass. Ingested food and drugs pass through the gastrojejunal anastomosis into the jejunum, effectively bypassing the absorptive surface area of the duodenum. Pancreatic and bile secretions still pass through the duodenum and into the jejunum through the jejunojejunal anastomosis, where they can mix with ingested food and drugs. Figure 1 Open in new tabDownload slide Rearranged digestive tract after Roux-en-Y gastric bypass. Ingested food and drugs pass through the gastrojejunal anastomosis into the jejunum, effectively bypassing the absorptive surface area of the duodenum. Pancreatic and bile secretions still pass through the duodenum and into the jejunum through the jejunojejunal anastomosis, where they can mix with ingested food and drugs. While the effects of RYGB on vitamin and nutrient absorption are well recognized,6–8 there is scant literature addressing its effect on the bioavailability of oral drugs. The majority of published case reports and small case–control studies attempting to address this paucity involved patients who had undergone BPD or JIB, procedures involving anatomical changes drastically different from those of RYGB.3 Some potential problems with drug absorption in the RYGB patient have been identified.3,9–13 However, little guidance is available on selecting therapeutic alternatives when drug absorption issues are identified in these patients. Utilizing the physiochemical properties of individual drugs or drug classes, such as the acid dissociation constant (pKa), partition coefficient (log P), and intestinal drug transporters, practitioners may be able to recommend better drug therapy regimens for their RYGB patients. Since RYGB is currently the preferred bariatric procedure performed, more pharmacokinetic clinical studies are needed to address the specific effect of RYGB on drug absorption. Until the results of such studies are available, clinicians should consider the physiochemical changes induced by RYGB and their potential effect on pharmacokinetic parameters in patients receiving drug therapy (Table 1). This knowledge could allow practitioners caring for RYGB patients to predict which drugs may have clinically significant changes in absorption characteristics and to select appropriate therapeutic alternatives. This article reviews the characteristics that may affect the pharmacokinetics of drugs in patients who have undergone RYGB. Potential effects on the pharmacokinetics of drug classes that may be commonly used in these patients are also described. Table 1 Potential Implications of RYGB on Drug Absorptiona Factor Pharmacokinetic Considerations Implications for RYGB Patients Surface area for drug absorption The villi and microvilli responsible for the vast absorptive surface in the small intestine are of highest concentration in the duodenum and proximal jejunum. The entire duodenum and a small portion of the proximal jejunum are bypassed, decreasing the effective surface area for drug absorption.7 Length of intestine and drug transit time Extended-release drug formulations were developed to slowly release drugs as they pass through the length of intestine. Since the entire duodenum and proximal jejunum are bypassed and motility through the intestine may be increased,9,10 these drugs may not have adequate transit time for full dissolution and absorption. Drug dissolution in acidic vs. alkaline environment Some drugs require an acidic environment for dissolution, activation, or absorption. In contrast, other drugs are degraded by acid; thus bioavailability is affected. Most of the parietal cells, the hydrochloric acid producers, are in the part of the stomach that has been bypassed, so the new stomach pH is increased to >4.11 The dissociation constant (pKa) and partition coefficient (log P) of a drug may be used to predict the effects of this change. Locations of drug transporters Various drug transporters carry drugs across the intestinal cell wall and into the circulation. Distribution of these transporters varies throughout the length of intestine. Some of the key transporters, metabolic enzymes, and efflux pumps occur with more frequency in the proximal small intestine, the area being bypassed. For example, Mct1, UGT, PST, GST, and MRP2 distribution favors the duodenum and jejunum over the ileum. Rate of gastric emptying Slowed gastric emptying may reduce the rate of drug absorption, as the delivery to the small intestine is prolonged. Creation of the small stomach pouch and the small anastomosis for food and drugs to pass through to the intestine promotes slowed gastric emptying.9,10 First-pass metabolism and enterohepatic recycling Drugs absorbed across the membrane of enterocytes enter the portal circulation and are delivered to the liver for metabolism (first-pass metabolism) before reaching the systemic circulation. Once in the systemic circulation, the drug eventually reaches the intestine again via mesenteric arteries. Here it gets reabsorbed across enterocytes into the portal circulation. This process repeats itself and is termed enterohepatic recycling. Some drugs, such as oral contraceptives, rely on this process for maintenance of steady-state blood levels. Drugs that rely on enterohepatic recycling for steady-state blood levels may have altered pharmacokinetic behavior or unpredictable blood levels due to decreased contact with the proximal intestine or altered mesenteric blood flow. Factor Pharmacokinetic Considerations Implications for RYGB Patients Surface area for drug absorption The villi and microvilli responsible for the vast absorptive surface in the small intestine are of highest concentration in the duodenum and proximal jejunum. The entire duodenum and a small portion of the proximal jejunum are bypassed, decreasing the effective surface area for drug absorption.7 Length of intestine and drug transit time Extended-release drug formulations were developed to slowly release drugs as they pass through the length of intestine. Since the entire duodenum and proximal jejunum are bypassed and motility through the intestine may be increased,9,10 these drugs may not have adequate transit time for full dissolution and absorption. Drug dissolution in acidic vs. alkaline environment Some drugs require an acidic environment for dissolution, activation, or absorption. In contrast, other drugs are degraded by acid; thus bioavailability is affected. Most of the parietal cells, the hydrochloric acid producers, are in the part of the stomach that has been bypassed, so the new stomach pH is increased to >4.11 The dissociation constant (pKa) and partition coefficient (log P) of a drug may be used to predict the effects of this change. Locations of drug transporters Various drug transporters carry drugs across the intestinal cell wall and into the circulation. Distribution of these transporters varies throughout the length of intestine. Some of the key transporters, metabolic enzymes, and efflux pumps occur with more frequency in the proximal small intestine, the area being bypassed. For example, Mct1, UGT, PST, GST, and MRP2 distribution favors the duodenum and jejunum over the ileum. Rate of gastric emptying Slowed gastric emptying may reduce the rate of drug absorption, as the delivery to the small intestine is prolonged. Creation of the small stomach pouch and the small anastomosis for food and drugs to pass through to the intestine promotes slowed gastric emptying.9,10 First-pass metabolism and enterohepatic recycling Drugs absorbed across the membrane of enterocytes enter the portal circulation and are delivered to the liver for metabolism (first-pass metabolism) before reaching the systemic circulation. Once in the systemic circulation, the drug eventually reaches the intestine again via mesenteric arteries. Here it gets reabsorbed across enterocytes into the portal circulation. This process repeats itself and is termed enterohepatic recycling. Some drugs, such as oral contraceptives, rely on this process for maintenance of steady-state blood levels. Drugs that rely on enterohepatic recycling for steady-state blood levels may have altered pharmacokinetic behavior or unpredictable blood levels due to decreased contact with the proximal intestine or altered mesenteric blood flow. a RYGB = Roux-en-Y gastric bypass, Mct1 = monocarboxylic acid transporter 1, UGT = glucuronosyltransferase, PST = sulfotransferase, GST = glutathione S-transferases, and MRP2 = multidrug-resistance-associated protein 2. Open in new tab Table 1 Potential Implications of RYGB on Drug Absorptiona Factor Pharmacokinetic Considerations Implications for RYGB Patients Surface area for drug absorption The villi and microvilli responsible for the vast absorptive surface in the small intestine are of highest concentration in the duodenum and proximal jejunum. The entire duodenum and a small portion of the proximal jejunum are bypassed, decreasing the effective surface area for drug absorption.7 Length of intestine and drug transit time Extended-release drug formulations were developed to slowly release drugs as they pass through the length of intestine. Since the entire duodenum and proximal jejunum are bypassed and motility through the intestine may be increased,9,10 these drugs may not have adequate transit time for full dissolution and absorption. Drug dissolution in acidic vs. alkaline environment Some drugs require an acidic environment for dissolution, activation, or absorption. In contrast, other drugs are degraded by acid; thus bioavailability is affected. Most of the parietal cells, the hydrochloric acid producers, are in the part of the stomach that has been bypassed, so the new stomach pH is increased to >4.11 The dissociation constant (pKa) and partition coefficient (log P) of a drug may be used to predict the effects of this change. Locations of drug transporters Various drug transporters carry drugs across the intestinal cell wall and into the circulation. Distribution of these transporters varies throughout the length of intestine. Some of the key transporters, metabolic enzymes, and efflux pumps occur with more frequency in the proximal small intestine, the area being bypassed. For example, Mct1, UGT, PST, GST, and MRP2 distribution favors the duodenum and jejunum over the ileum. Rate of gastric emptying Slowed gastric emptying may reduce the rate of drug absorption, as the delivery to the small intestine is prolonged. Creation of the small stomach pouch and the small anastomosis for food and drugs to pass through to the intestine promotes slowed gastric emptying.9,10 First-pass metabolism and enterohepatic recycling Drugs absorbed across the membrane of enterocytes enter the portal circulation and are delivered to the liver for metabolism (first-pass metabolism) before reaching the systemic circulation. Once in the systemic circulation, the drug eventually reaches the intestine again via mesenteric arteries. Here it gets reabsorbed across enterocytes into the portal circulation. This process repeats itself and is termed enterohepatic recycling. Some drugs, such as oral contraceptives, rely on this process for maintenance of steady-state blood levels. Drugs that rely on enterohepatic recycling for steady-state blood levels may have altered pharmacokinetic behavior or unpredictable blood levels due to decreased contact with the proximal intestine or altered mesenteric blood flow. Factor Pharmacokinetic Considerations Implications for RYGB Patients Surface area for drug absorption The villi and microvilli responsible for the vast absorptive surface in the small intestine are of highest concentration in the duodenum and proximal jejunum. The entire duodenum and a small portion of the proximal jejunum are bypassed, decreasing the effective surface area for drug absorption.7 Length of intestine and drug transit time Extended-release drug formulations were developed to slowly release drugs as they pass through the length of intestine. Since the entire duodenum and proximal jejunum are bypassed and motility through the intestine may be increased,9,10 these drugs may not have adequate transit time for full dissolution and absorption. Drug dissolution in acidic vs. alkaline environment Some drugs require an acidic environment for dissolution, activation, or absorption. In contrast, other drugs are degraded by acid; thus bioavailability is affected. Most of the parietal cells, the hydrochloric acid producers, are in the part of the stomach that has been bypassed, so the new stomach pH is increased to >4.11 The dissociation constant (pKa) and partition coefficient (log P) of a drug may be used to predict the effects of this change. Locations of drug transporters Various drug transporters carry drugs across the intestinal cell wall and into the circulation. Distribution of these transporters varies throughout the length of intestine. Some of the key transporters, metabolic enzymes, and efflux pumps occur with more frequency in the proximal small intestine, the area being bypassed. For example, Mct1, UGT, PST, GST, and MRP2 distribution favors the duodenum and jejunum over the ileum. Rate of gastric emptying Slowed gastric emptying may reduce the rate of drug absorption, as the delivery to the small intestine is prolonged. Creation of the small stomach pouch and the small anastomosis for food and drugs to pass through to the intestine promotes slowed gastric emptying.9,10 First-pass metabolism and enterohepatic recycling Drugs absorbed across the membrane of enterocytes enter the portal circulation and are delivered to the liver for metabolism (first-pass metabolism) before reaching the systemic circulation. Once in the systemic circulation, the drug eventually reaches the intestine again via mesenteric arteries. Here it gets reabsorbed across enterocytes into the portal circulation. This process repeats itself and is termed enterohepatic recycling. Some drugs, such as oral contraceptives, rely on this process for maintenance of steady-state blood levels. Drugs that rely on enterohepatic recycling for steady-state blood levels may have altered pharmacokinetic behavior or unpredictable blood levels due to decreased contact with the proximal intestine or altered mesenteric blood flow. a RYGB = Roux-en-Y gastric bypass, Mct1 = monocarboxylic acid transporter 1, UGT = glucuronosyltransferase, PST = sulfotransferase, GST = glutathione S-transferases, and MRP2 = multidrug-resistance-associated protein 2. Open in new tab Factors affecting pharmacokinetics in RYGB patients Intestinal drug transporters When an orally administered drug dissolves, it must cross the intestinal wall, reach the liver via the portal circulation, and then enter the systemic circulation to distribute into various tissues in the body. Only un-ionized drug can passively diffuse across cell membranes. Ionized drugs may require active transport across cell membranes via transporter proteins. Transporter proteins are typically located at the apical or basolateral surfaces of enterocytes and can play a role in either influx or efflux of drugs from cells (Figure 2).14 Drugs have predetermined affinities for various transporter proteins, and their interactions with the transporters help determine the extent of drug absorption in the small intestine. These transporters are not always located homogeneously throughout the length of the small intestine. It can be hypothesized that those transporters that are more frequently found in the duodenum and upper jejunum play a role in decreased drug absorption in the RYGB patient. Those transporters occurring more frequently in the distal jejunum and ileum may have less of an effect, if any, on drug absorption, since these segments are not surgically altered during RYGB. Figure 2 Open in new tabDownload slide Schematic diagram of an enterocyte showing absorptive and efflux drug transporters as well as intracellular metabolic enzymes.14 PEPT-1 = peptide transporter 1, OATP = organic anion-transporting polypeptide, BCRP = breast cancer resistance protein, MRP2 = multidrug-resistance-associated protein 2, CYP = cytochrome P-450, UGT = uridine diphosphate-glucuronosyltranferase, PST = phenol-sulfotransferase, GST = glutathione S-transferase. Figure 2 Open in new tabDownload slide Schematic diagram of an enterocyte showing absorptive and efflux drug transporters as well as intracellular metabolic enzymes.14 PEPT-1 = peptide transporter 1, OATP = organic anion-transporting polypeptide, BCRP = breast cancer resistance protein, MRP2 = multidrug-resistance-associated protein 2, CYP = cytochrome P-450, UGT = uridine diphosphate-glucuronosyltranferase, PST = phenol-sulfotransferase, GST = glutathione S-transferase. The organic anion transporting polypeptides (OATPs) are a family of influx transporters expressed in various tissues and are important determinants of anionic drug absorption.14,15 Specifically, origins of the OATP isoforms (OATP2B1 and OATP1A2) have been reported to be located on the apical surface of human enterocytes, with the highest level of expression in the jejunum.16 Erythromycin, fexofenadine, levofloxacin, thyroxine, and several hydroxymethylglutaryl–coenzyme A reductase inhibitors have been shown to interact with these transporters.16 Since only a small portion of jejunum is bypassed during RYGB, it is unknown if drugs dependent on this transporter will have impaired absorption. Another example of an influx transporter is the oligopeptide transporter (PEPT-1). It is located in the intestinal brush-border membrane.17,18 PEPT-1 has been shown to be involved with the absorption of dipeptides and tripeptides or peptidomimetic drugs. This characteristic becomes clinically important as certain antibiotics (i.e., β-lactams, including cephalosporins) and angiotensin-converting-enzyme inhibitors, shown to be structurally similar to peptides, have an affinity for the intestinal PEPT-1.17,18 Examples of oral cephalosporins shown to rely heavily on this transporter include cefadroxil, cefaclor, cefuroxime, cefixime, and cephalexin.19 The reduction in the functional small intestine length caused by RYGB could reduce the amount of functional PEPT-1, because it is found more frequently in the duodenum and jejunum than in the ileum. The absorption of drugs that depend on PEPT-1 may be decreased in patients who have undergone RYGB. P-glycoprotein, also referred to as multidrug-resistance protein 1, is an example of an efflux transporter that is located on the apical membrane of intestinal enterocytes. Its expression increases from the stomach toward the colon.20 Substrates for P-glycoprotein (e.g., digoxin, verapamil, diltiazem, sotalol) flow from enterocytes back into the intestinal lumen.21 Under normal physiological conditions, drug flowing out of the enterocyte by P-glycoprotein back into the intestinal lumen can be reabsorbed at a distal site and subjected to the same fate. The expression of P-glycoprotein may be altered in patients with a decreased functional length of the small intestine, but this event is not as likely given that the P-glycoprotein efflux pump is found in higher concentrations in the jejunum and ileum than in the duodenum. Metabolizing enzymes Intestinal tissue is rich with metabolic phase I and II enzymes, albeit at lower levels than in hepatic tissue. The drug-metabolizing enzymes uridine diphosphate-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases decrease in concentration throughout the length of small intestine, from duodenum to ileum.22 It is unknown if bypassing the higher concentration of these enzymes in the duodenum would affect drug absorption and metabolism in patients who have undergone RYGB. The concentration of human intestinal cytochrome P-450 isoenzyme 3A4 is highest in the jejunum, so its function would expectedly be preserved in RYGB patients but has yet to be proven in clinical pharmacokinetic studies. Likewise, the multidrug- resistance-associated protein 2 (MRP2) transporter plays an important role in the absorption of glucuronide conjugates. Most glucuronide conjugates are metabolites of drugs that are readily excreted. MRP2 is located primarily in the duodenum and jejunum; therefore, its functionality may be compromised in patients who have undergone RYGB, potentially leading to an accumulation of glucuronide metabolites. However, it is unclear if there is enough MRP2 in the remaining jejunum to perform all necessary glucuronidation. In other words, the MRP2 being bypassed in the duodenum may not be missed as long as the jejunal MRP2 is not overwhelmed with substrate. Log P and pH The pH of a solution is a logarithmic scale measurement of its acidity or alkalinity on a scale of 0–14. As the number of protons in a solution increases, the pH value decreases. As the amount of hydroxide, or basicity, in a solution increases, the pH value increases. In a healthy patient, the stomach pH ranges from 1 to 3 due to the gastric hydrochloric acid pumps, which force protons into the stomach. Patients who have had RYGB have significantly fewer pumps in the small pouch formed during surgery. As a result, there are significantly fewer protons being forced into the stomach; therefore, the pH of the stomach of RYGB patients will be closer to the acidity of the intestine. The strength of an acidic or basic functional group in a drug molecule is measured by the pKa. The lower the value, the more acidic the functional group (higher extent of proton dissociation), whereas a high value means the functional group of interest has an increased ability to act as a base (lower extent of proton dissociation).23 For reference, a carboxylic acid has a pKa of roughly 4, and a primary amine has a pKa of roughly 10. By employing the Henderson-Hasselbach equation, it is possible to calculate the amount of ionized to un-ionized drug species at any given pH.23 In general, if the pKa of a drug is lower than the pH of the solution it is in, then the water in the body is a better base than the functional group of interest. The functional group with the lower pKa will then give up its proton to the water in the body, and it will have a negative charge. If the pKa of the functional group is higher than the pH of the water in the body, such as an amine functional group, then the amine is a better base. In this situation, the amine will take a proton from the water, and the functional group will have a positive charge. The charged species of a drug will predominately require the assistance of a transporter to move the drug across the intestinal membrane and into the blood. When considering the bioavailability of a compound, remember the old adage “like attracts like.” An uncharged, or neutral, drug will more readily diffuse through the hydrophobic membrane of the intestine.23,24 To measure the preference of a drug for a hydrophobic versus hydrophilic environment, the log scale partition coefficient of a drug between water and octanol is determined experimentally.23,25 This partition value is called log P, and a low value means the drug prefers to be in the hydrophobic octanol environment. When a drug has a low log P value, it can more easily cross the intestinal membrane without the use of drug transporters but will suffer from reduced solubility in water and may require emulsifying agents.23–25 Log P values of most drugs are determined in a controlled environment most closely resembling the normal human gastrointestinal tract and will vary if the environment changes. Therefore, the increased pH of the stomach and upper intestine of a patient who has undergone RYGB may affect the amount of ionized drug present, which could affect the log P value. Optimum absorption of a drug through the gastrointestinal tract occurs with log P values of 1–2. If the drug becomes more ionized or charged, which can be determined from the Henderson-Hasselbach equation, then the log P would be expected to rise.23,25 Considerations for specific drug classes Analgesics In the general population, the use of nonsteroidal antiinflammatory drugs (NSAIDs) is linked to ulcers in 15–30% of patients after long-term administration.26 Due to the smaller stomach pouch and the importance of maintaining staple-line integrity, ulcers in the RYGB patient are very detrimental; therefore, these drugs are generally avoided in these patients. However, if NSAIDs must be used, the following physiochemical principles warrant consideration. NSAIDs are weak acids with pKa values ranging from 3 to 5 and, in the normal physiological stomach (pH, 1–3), remain un-ionized until they reach the small intestine.27 In patients who have undergone RYGB, the pH of the stomach increases to approximately 5 and makes NSAIDs more ionized (when the pKa equals the pH, 50% of the drug is ionized). This change in pH increases the solubility of NSAIDs in the stomach through faster tablet dissolution. Thus, more drug is available for passive absorption once it reaches the intestinal membrane.28 This physiological change could increase the risk of ulcers and erosion, since more liberated drug may be present. Ulcers in the RYGB patient are a difficult complication to treat as they often occur at anatomosis sites, which, if not diagnosed or treated in a timely manner, can lead to gastric outlet obstruction or fistulas that require reoperation. In contrast, acetaminophen has a pKa of 9.51 in water, meaning that a shift in stomach pH up to 5–6 will not affect the drug’s ionization.23,27 Acetaminophen has a bioavailability of 60–98% and is rapidly absorbed in patients with normal gastrointestinal physiology.27 The main site of absorption of acetaminophen is the jejunum, distal from the duodenojejunal flexure.29 This part of the intestine is maintained in patients after RYGB, making it unlikely to have an impact on absorption. This absorption mechanism makes acetaminophen a good analgesic option for patients who have undergone RYGB. Another good option for consideration is the use of the analgesic tramadol. Tramadol has a pKa of 9.41, similar to that of acetaminophen, so it is not likely to be affected by the increased pH of the new stomach pouch. Its log P value is 1.35 at pH 7, making it relatively soluble in water, accounting for its bioavailability of 75%.27 Tramadol is not highly lipophilic; therefore, it is less likely to be affected by an alteration in pH, because its absorption is not dependent on the availability of bile acids to enhance its solubility.6 In the RYGB environment, bile acids are still allowed to interact with orally administered drugs, but the process occurs further down in the jejunum. Moreover, RYGB patients are on restrictive diets, and the amount of bile acids secreted into the intestinal tract is variable. The effect of these bile acid factors combined is unknown in patients who have undergone RYGB. Antibiotics Fluoroquinolones are rapidly absorbed, and their mechanism of absorption relies less on gastric acidity and more on small intestine transport mechanisms, similar to the absorption of macrolides.30 Recently, a classwide mechanism for absorption has been identified involving the OATP influx transporter in the small intestine using the drug levofloxacin.16 Therefore, a reduction in the absorption of fluoroquinolones could be possible if exposure of the drug to OATPs is reduced in RYGB patients. Antiarrhythmics Patients with RYGB are likely to have other underlying comorbidities, such as arrhythmias, that require long-term treatment. The absorptive properties of antiarrhythmics carry important clinical implications due to the narrow therapeutic indexes of these drugs. Malabsorption of these drugs could lead to the recurrence or exacerbation of arrhythmias. Amiodarone is a weak acid (pKa = 5.6), and its bioavailability varies greatly (22–86%) in patients with a preserved gastrointestinal tract.30 Its absorptive process is by passive diffusion mechanisms that are driven largely by its lipophilic nature and low aqueous solubility. Since amiodarone is poorly soluble, the intestinal transit time affects its bioavailability.31 Intestinal transit time is shortened in RYGB patients; therefore, the bioavailability of amiodarone could be changed as well. Furthermore, since amiodarone is a highly lipophilic drug, its absorption depends on bile salts to enhance its solubility.31 The bioavailability of drugs with an intrinsically low bioavailability after oral administration could be lower in patients with an altered gastrointestinal physiology, such as a patient who has undergone RYGB. Digoxin has a bioavailability ranging from 60% to 85% after oral administration.28 It is very water soluble, with a log P value of 1.04; however, due to its high molecular weight, drug liberation from the tablet is low and highly dependent on gastric residence time to increase its solubility.28 Furthermore, digoxin is a substrate for P-glycoprotein in the small intestine. Similar to macrolide antibiotics that are also substrates for this efflux mechanism in the small intestine, there may be less opportunity for the drug to be pumped out of the basolateral membrane of intestinal enterocytes.32 This change in exposure to P-glycoprotein could have an effect on the extent of digoxin absorption. Anticoagulants Warfarin is a weak acid with a pKa of 5.05 and is predominantly un-ionized at a normal stomach pH. It is extensively absorbed through the stomach and proximal small intestine.33 This chemical property would make absorption more dependent on exposure to the gastrointestinal tract. It has been suggested that the reduced intestinal surface area in RYGB patients may decrease the absorption of warfarin.33 One published case report has described decreased warfarin absorption in a patient after RYGB.34 On the other hand, moving to a more alkaline stomach (pH, 4–6) could make the ratio of un-ionized:ionized warfarin closer to 1:1; therefore, more drug will be un-ionized in the stomach and readily available for passive absorption. RYGB patients are also susceptible to nutrient deficiencies of fat-soluble vitamins (vitamins A, D, E, and K). Vitamin K deficiency may lead to a decrease in vitamin-K-dependent clotting factors and could have an effect on warfarin dosage requirements in patients who have undergone RYGB. Discussion Given the lack of guidance in the literature regarding drug absorption after RYGB, it is important for practitioners caring for this population to be able to predict possible factors affecting drug absorption. Basic concepts outlining how drug absorption may be affected are available, but predicting the absorption of individual drugs or drug classes requires a more in-depth look at mechanisms of drug absorption. Utilizing drug properties such as pKa, log P, and drug transporters employed can help practitioners select more appropriate drug therapy for the gastric bypass patient. Because drug absorption relies on several mechanisms, caution must be exercised to avoid considering only one factor, such as pKa, while ignoring another factor, such as the role of intestinal drug transporters. Solubility information for drugs (e.g., pKa, log P) can sometimes be found in the prescribing information, drug information resources (e.g., Micromedex Healthcare Series, Thomson Reuters Healthcare, Greenwood Village, CO), pharmacology or medicinal chemistry textbooks, or primary physiochemical studies with the specific drug. Information on specific drug transporters involved in the drug’s absorption, if available, is most likely found in the primary literature. Oral drug absorption is a complex process in the normal human gastrointestinal tract, let alone the RYGB environment. Future studies should focus on widely used oral drugs for conditions not commonly improved or resolved with bariatric surgery, such as antidepressants, antipsychotics, antiarrhythmics, anticoagulants, antibiotics, hormonal modifiers, and anticonvulsants. Since hypertension, type 2 diabetes mellitus, and hyperlipidemia are often resolved or dramatically improved with successful bariatric surgery, absorption studies involving drugs for these conditions may not be as clinically useful. Conclusion The pKa, log P, and intestinal transport mechanisms should be considered when determining which drugs may have altered pharmacokinetics in patients who have undergone RYGB. 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TI - Pharmacokinetic considerations in Roux-en-Y gastric bypass patients
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp100630
DA - 2011-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pharmacokinetic-considerations-in-roux-en-y-gastric-bypass-patients-BNKSvgNOuo
SP - 2241
VL - 68
IS - 23
DP - DeepDyve
ER -