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Journal of Clinical Pharmacology, 2003; 43:996-1002
© 2003 the American College of Clinical Pharmacology

PHARMACOKINETICS AND PHARMACODYNAMICS

Gastric Function in the Elderly: Effects on Absorption of Ketoconazole

Aryeh Hurwitz, MD, Constance E. Ruhl, MD, MPH, Bruce F. Kimler, PhD, Elizabeth M. Topp, PhD and Matthew S. Mayo, PhD

From the University of Kansas Medical Center, Department of Medicine (Dr. Hurwitz), Center on Aging (Dr. Ruhl), Department of Radiation Oncology (Dr. Kimler), Kansas Cancer Institute (Dr. Mayo), and Department of Preventive Medicine (Dr. Mayo), Kansas City, Kansas, and the University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, Kansas (Dr. Topp).

Address for reprints: Aryeh Hurwitz, MD, Department of Internal Medicine, Division of Clinical Pharmacology, Room 4016 Wescoe, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7320.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The authors studied effects of age-related changes in gastric function on absorption of ketoconazole. Eighteen men and women age 65 years or older swallowed 200 mg ketoconazole on two occasions, once as tablets with water and once as tablets crushed in acidic juice. The sequence was randomly determined. Gastric pH was measured by radiotelemetry and gastric emptying rate by radiolabeled technetium with a gamma camera. Plasma ketoconazole was assayed by high-performance liquid chromatography (HPLC). Subjects with gastric pH less than or equal to 4.5 absorbed ketoconazole equally well from intact tablets and tablets crushed in acid. When pH was 5.0 or higher, ketoconazole was absorbed well from acid-crushed tablets but not from intact tablets. Gastric emptying was shown to be rapid in all subjects. Since the prevalence of such hypoacidity is approximately 5% in the elderly, and other parameters of gastric function are usually normal, impaired absorption of drugs such as ketoconazole should be uncommon with normal aging.

Key Words: Ketoconazole • gastric function • drug absorption • pharmacokinetics • elderly patients

The elderly ingest more drugs per capita than the rest of the population.1 Age-related changes in physiology have been postulated to cause differences in disposition and pharmacokinetics of orally administered drugs. Among factors felt to affect absorption of drugs from swallowed tablets are age-related changes in gastric emptying and acid secretion and in intestinal surface area and blood flow.2 Rates of disintegration, dissolution, or gastric emptying may limit the rate and extent of absorption from solid dosage forms. The present study was undertaken to find out if gastric functions in elderly people—specifically, gastric acidity and emptying—are sufficiently altered to affect drug absorption.

Among drugs affected by gastric pH is the antifungal agent, ketoconazole, which is insoluble in aqueous medium at pH 5.0 or higher.3,4 Since ketoconazole was introduced in the early 1980s, the need for gastric acid to absorb ketoconazole has been well known. Its manufacturer has recommended that "in cases of achlorhydria, the patients should be advised to dissolve each tablet in 4 mL aqueous solution of 0.2 N HCl" and to "use a drinking straw so as to avoid contact with the teeth." The use of an acidic cola drink5 has been recommended for enhancing ketoconazole absorption in patients suspected to have achlorhydria, which has been interpreted as including the elderly.6 One recent review7 stated that "secretion of gastric acid decreases with advancing age" and cited ketoconazole as a drug "absorbed better in acid medium." This same review also noted that "few studies have assessed drug absorption in elderly patients." The present study is the first to evaluate ketoconazole absorption in the elderly directly, specifically relating absorption to gastric factors, such as emptying and acidity.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Sample
Eighteen nonobese, nonsmoking men and women age 65 years and older were recruited from a retirement community in a suburb of Kansas City, Missouri. All of the subjects, who were living independently and caring for themselves, had chronic medical conditions requiring drug treatment (Table I). The subjects had participated in an earlier study of gastric acidity8 and were selected for the present study based on their gastric secretory status as determined in that study. All the subjects were fully informed and signed a consent instrument approved by the Human Subjects Committees of the University of Kansas Medical Center and of John Knox Village, Lee's Summit, Missouri.


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  		Table I Characteristics of Study Population

 

The subjects came to Lee's Summit Hospital, Lee's Summit, Missouri, on the morning of each study after fasting overnight, having skipped their morning medications. After they had a brief review of medical status and a physical examination, a Teflon venous cannula with a heparin lock was inserted. A baseline blood sample was obtained, and a belt antenna was placed around the waist for pH monitoring. While lying supine in a semirecumbent position under a gamma camera, the subject swallowed a precalibrated Heidelberg pH radiotelemetry capsule with 60 mL water for determining gastric pH.8 Then ketoconazole, 200 mg, was swallowed, either as a tablet with 80 mL water or crushed in 10 mL 0.1 N HCl plus 50 mL citrus juice. This was followed by swallowing radiolabeled DTPA, as described below, for assessment of gastric emptying. Gastric emptying was recorded for 1 hour and pH for 2 hours. Heparinized blood samples were obtained from the venous cannula at 0 (predose) and 0.5, 1, 2, 5, and 8 hours after ketoconazole ingestion. If difficulty was encountered with the venous cannula, it was removed, and a single blood sample was obtained by direct venipuncture at 2 hours after ingestion of ketoconazole.

Each subject underwent two ketoconazole studies: intact tablet with water and crushed tablet in acid. The sequence of the two studies, done 1 to 2 weeks apart, was randomly determined.

Gastric Emptying of Radiolabeled 99mTechnetium-DTPA in Water
While lying semirecumbent under a gamma camera, the subject drank 60 mL water containing 100 µCi 99mTechnetium-DTPA (99mTc-DTPA).9 The total volume of water swallowed was 180 mL. Disappearance of isotope from the stomach was recorded with the gamma camera-computer combination (Siemens LFOV with MDS-A2 computer) for the next hour. In the analysis phase, a region of interest was selected encompassing the stomach. Data were corrected for isotope decay and reexpressed in terms of logarithm of counts versus time. A least squares fit of the data was used to compute the half-emptying time. The radiation exposure was well below the recommended allowable limits for the general population.

Ketoconazole Assay
Plasma samples that had been frozen at -20°C were thawed and ketoconazole assayed by a modification of the method of Pascucci et al.10 After addition of the internal standard, phenothiazine, an equal volume of 0.1 N sodium hydroxide was added, and an aliquot was applied to an Alltech Extract-Clean C-18 column. The column was washed with water and eluted with methanol. The eluate was evaporated and reconstituted in methanol. An aliquot was injected onto a Rainin Microsorb MV 5 µ C-18 column with an Alltech SSI 0.5-µm column prefilter. The column was eluted with a mobile phase of 75% methanol/25% 0.02 M monobasic sodium phosphate, pH 6.6, at a flow rate of 1.25 mL/min. Peaks were detected on a variable wave-length Schoeffel fluorometer set at excitation of 206 nm and emission at 370 nm. Peak areas of ketoconazole and phenothiazine were measured and recorded by a Shimadzu Model CR501 data-handling system.

Pepsinogen Assay
Pepsinogen I (PGI) and pepsinogen II (PGII) in serum were assayed by radioimmunoassay.11 A serum PGI/PGII ratio less than 2.9 indicated atrophic gastritis.12

Pharmacokinetic and Statistical Calculations
Pharmacokinetic parameters were determined by inspection (tmax = time to peak, Cmax = concentration at peak) and by the trapezoidal rule (AUC0-8 = area under the plasma concentration-time curve from 0 to 8 h). Correlations between pharmacokinetic parameters (Cmax,C2h, AUC0-8) were calculated by Spearman's rank correlation. The Wilcoxon rank-sum test was used to assess differences between secretors and nonsecretors of acid. The Wilcoxon signed-rank test was used to assess paired differences.13


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Absorption of ketoconazole from intact tablets was impaired in hyposecretors of gastric acid. In subjects with basal gastric pH of 5.0 or higher, plasma ketoconazole concentrations were significantly lower at 2 hours after swallowing ketoconazole tablets with water than in subjects with lower gastric pH (Figure 1). When these hyposecretors swallowed tablets crushed in acid, they achieved plasma ketoconazole concentrations similar to those in acid secretors, in whom there was no difference between absorption from intact and acid-crushed tablets. The critical requirement of gastric pH below 5.0 for absorption of ketoconazole from intact tablets is shown in Figure 2a. In 5 of 6 subjects with basal gastric pH of 5.0 or higher, plasma ketoconazole concentrations 2 hours after swallowing tablets with water were 1.0 µg/mL or lower; 11 of 12 subjects with basal pH less than 5.0 had higher ketoconazole concentrations (p < 0.02). Although crushing tablets in acid had no consistent effect when basal pH was below 5.0, all 6 subjects with lower acidity absorbed drug less effectively from intact tablets taken with water (water/acid ratio below 1.0 in Figure 2b) (p < 0.005). Concentrations of ketoconazole in plasma at 2 hours correlated strongly with peak levels (r = 0.85 and 0.97 for acid and water, respectively; p < 0.001 for both) and with AUC0-8 (r = 0.73 and 0.96 for acid and water, respectively; p < 0.001 for both). Gastric acidity affected absorption (AUC0-8) similarly in the 12 subjects (7 acid secretors, 5 hyposecretors) in whom complete 8-hour blood collections could be obtained (Figure 3) and, based on the 2-hour plasma concentrations, in the entire study population of 18 subjects (12 acid secretors, 6 hyposecretors). When hyposecretors ingested ketoconazole tablets with water, their plasma drug concentrations were lower than those of acid secretors (p < 0.05 at 1 and 2 h). When hyposecretors ingested tablets crushed in acid, their plasma ketoconazole concentrations were significantly higher at each time point (up to 8 h) than the concentrations resulting from their ingestion of intact tablets with water.



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  		Figure 1. Median values and upper and lower quartile ranges of plasma ketoconazole concentrations 2 hours after ingesting tablets with water ({blacksquare}) or crushed in acid (•). Subjects with basal pH < 5.0 are shown to the left (n = 12) and hyposecretors with pH >= 5.0 are to the right (n = 6). *p < 0.05.

 


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  		Figure 2. (a) Plasma ketoconazole concentrations 2 hours after ingesting intact tablets with water as a function of basal gastric pH. (b) Ratios of 2-hour ketoconazole plasma concentrations after ingestion of tablets with water to concentrations from tablets crushed in acid.

 


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  		Figure 3. Plasma ketoconazole concentrations at times after administration. Subjects with baseline pH of >= 5.0 (n = 5) are shown in the upper panel, and those with pH < 5.0 (n = 7) are shown in the lower panel. Ketoconazole was administered as a tablet in water (•) and as a suspension in acid ({blacksquare}). Data are means ± SE.

 

Other measures of gastric function were determined in the course of the drug absorption studies. Ingestion of ketoconazole with acid slowed emptying of liquid (99mTc-DTPA) similarly in acid secretors and in hyposecretors (Table II). Passage of a solid, the pH detection capsule, out of an acid-containing stomach was noted by a sharp rise in pH. After acid ingestion, no difference in passage of the capsule could be shown between acid secretors and hyposecretors. Passage of the capsule out of the stomach could not be ascertained in hyposecretors when they swallowed the intact tablets with water since their basal gastric-duodenal pH gradient was insufficient to indicate capsule passage.


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  		Table II Gastric Function in Secretors and Hyposecretors

 

Hyposecretors, whose basal gastric pH was equal to or higher than 5.0 after swallowing water with ketoconazole tablets, had lower ratios of pepsinogen I to pepsinogen II in serum (Table II), indicating a greater extent of atrophic gastritis. Three of 6 hyposecretors had pepsinogen ratios below 2.9, consistent with atrophic gastritis12; all but 1 of 12 subjects with more basal acid had ratios above this value.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
It has long been assumed that gastrointestinal absorption of orally administered drugs must be impaired in the elderly as a result of age-related changes in gastrointestinal function.2,14,15 This belief is based in part on numerous reports, starting in 1924, that the stomach stops secreting acid as people age.16,17 Some drugs require acid for the solid dosage form to disintegrate, dissolve, and be absorbed. In the present study, the pharmacokinetics of one such drug, ketoconazole, were examined in elderly people to determine which aspects of their gastric function, such as gastric acidity and emptying, affect its plasma concentrations after oral ingestion. Ketoconazole was chosen since its absorption is known to depend on gastric pH. Tablets of ketoconazole disintegrate independently of pH, but dissolution falls off drastically as pH is raised above the critical level of 5.0.3,4 Studies in vitro in aqueous solutions and in simulated gastric fluid have shown that ketoconazole is soluble in acidic solutions but precipitates when pH exceeds this critical value. Our present finding, that ketoconazole plasma levels were not reduced in older people until gastric pH was 5.0 or higher, agrees with these in vitro results and with findings in young healthy male volunteers given ranitidine to suppress acid secretion.18 In our elderly subjects with gastric pH below 5.0, additional hydrochloric acid did not further enhance ketoconazole absorption.

Recent reports show that older people do secrete gastric acid, contradicting the earlier data. In two of these studies, the prevalence of achlorhydria in the elderly was similar to that reported in healthy younger adults. Russell et al19 found that only 9 of 79 (11%) healthy elderly subjects (mean age 71 years) had fasting gastric pH of 5.0 or above. In 4 of these 9 subjects, gastric pH fell after a meal, indicating that all but 6% (5 of 79) were able to secrete acid in response to a stimulus. A more recent study found that only 11% of 248 elderly people (median age 79) with the usual diseases found in this population consistently had gastric pH above 3.5.8 Direct measurement of gastric pH by telemetry in a subgroup of this population showed that more than half had gastric pH between 3.5 and 4.5. Thus, fewer than 5% of elderly people would be expected to have gastric pH >= 5.0, hypoacidity sufficient to impair ketoconazole absorption.

While there is very little evidence to correlate higher concentrations of ketoconazole in blood with increased clinical response, there is a clear association of poor response with levels below a minimum threshold.20 In nearly all our hyposecretors, plasma ketoconazole concentrations from intact tablets would have been subtherapeutic. Such low levels had been found when ketoconazole5,6,21,22 or itraconazole23 was administered to younger people together with drugs that suppress or neutralize gastric acid and in patients with achlorhydria due to diseases such as AIDS and other immunosuppressed states.24,25 These patients have been advised to ingest ketoconazole with acid to enhance its absorption. Crushing of tablets in dilute hydrochloric acid has been recommended,26 but this is inconvenient, is unpalatable, and damages dental enamel while irritating the oropharyngeal mucosa. On the basis of the present study and our previous data showing low prevalence of gastric pH above 5.0, we question the general advisability of this recommendation to the elderly who take ketoconazole.

Gastric hypoacidity has been implicated as a cause of malabsorption of some nutrients and drugs in addition to ketoconazole and itraconazole. These include cinnarizine, enoxacin, cefpodoxime proxetil, and dipyridamole.27 Since the critical pH for dissolution and absorption of these drugs may differ from 5.0, which defines hypoacidity for ketoconazole, no generalization can be accurately made regarding gastric secretion in the elderly and drug absorption. Absorption of certain formulations of tetracycline28 and ampicillin29 was reduced by gastric hypoacidity, but this could be overcome by administering formulations with better bioavailability.30-33 Thus, acid is not inherently needed for absorption of these two drugs, unlike the case with ketoconazole.

In addition to gastric acidity, other physiological factors could change with age and affect drug absorption. Since most absorption normally takes place distal to the stomach in the small intestine, delay in gastric emptying and reduction of intestinal mucosal surface area or blood flow could reduce the rate or extent of absorption. In the present study, subjects remained in a constant semirecumbent position to minimize the effects of gravity on motility or blood flow.34,35 Our data show that gastric emptying of the drug-containing aqueous phase in the elderly was as rapid as that reported in healthy younger adults,15 being slowed slightly by added acid, as expected.36 Orange and grapefruit juices, which were used to mask the taste of tablets crushed in acid, are known to affect absorption and metabolism of drugs.37-40 However, grapefruit juice does not raise plasma concentrations of itraconazole,41,42 an azole antifungal with absorption and metabolism nearly identical to ketoconazole's, and did not raise ketoconazole levels in our elderly subjects who secreted acid. This suggests that acid, not juice, enhanced absorption in subjects with achlorhydria. While ketoconazole is well absorbed after oral administration, we confirmed large inter- and intraindividual variations in peak plasma ketoconazole concentrations after the same oral dose.5,43

The present study demonstrates that plasma levels of a drug with acid-dependent dissolution may be subtherapeutic in elderly people with achlorhydria, as had been shown in other populations with gastric pH near neutral. However, recent studies44,45 have shown that achlorhydria and other physiological causes of malabsorption are uncommon in the elderly; gastric acid secretion in humans changes little with aging, unless there is coexistent gastric pathology.46 Indeed, once gastric acidity was restored in our hyposecretors, ketoconazole plasma concentrations in elderly subjects were in the same range as reported in earlier studies in healthy volunteers.5,43 This suggests that age-related changes in other gastrointestinal functions did not limit the rate or extent of drug absorption.

In the small number of patients in whom atrophic gastritis is expected (e.g., those with pernicious anemia or immunosuppression), measures may have to be taken to avoid therapeutic failure with the limited number of drugs that display acid-dependent dissolution. In such patients, acid supplementation (cola drink) or drug substitution (fluconazole instead of ketoconazole4,47) may be required. Interactions with other drugs, including acid suppressants such as proton pump inhibitors,48 are more likely than age-related changes in gastrointestinal function to lower plasma concentrations of ketoconazole below therapeutic levels. In other instances of inadequate drug response, poor compliance has to be considered as the most likely cause.49-51


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Supported by USPHS Grant RO1AG02780 and John Knox Village and Lee's Summit Hospital, Lee's Summit, Missouri. I. M. Samloff, MD, performed the serum pepsinogen assays.


   FOOTNOTES
 
DOI: 10.1177/0091270003255645

Submitted for publication December 29, 2002; Revised version accepted April 28, 2003.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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