Pharmacokinetics in Roux-en-Y Gastric Bypass Patients

Abstract and Introduction

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 pK_a 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 pK_a, log P, and intestinal transport mechanisms should be considered when determining which drugs may have altered pharmacokinetics in patients who have undergone RYGB.

Introduction

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.

(Enlarge Image)

Figure 1.

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,^[6,7,8] 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 (pK_a), 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 (pK_a) 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.

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 (pK_a) 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.

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