Rosemary R. Berardi

Upper Gastrointestinal (GI) pH in Young, Healthy Men and Women

The pH in the upper gastrointestinal tract of young, healthy men and women was measured in the fasting state and after administration of a standard solid and liquid meal. Calibrated Heidelberg capsules were used to record the pH continuously over the study period of approximately 6 hr. In the fasted state, the median gastric pH was 1.7 and the median duodenal pH was 6.1. When the meal was administered the gastric pH climbed briefly to a median peak value of 6.7, then declined gradually back to the fasted state value over a period of less than 2 hr. In contrast to the pH behavior in the stomach, feeding a meal caused a reduction in the median duodenal pH to 5.4. In addition, there was considerable fluctuation in the postprandial duodenal pH on an intrasubject basis. The pH in the duodenum did not return to fasted state values within the 4-hr postprandial observation period. There was no tendency for the duodenal pH to be related to the gastric pH in either the fed or fasted phases of the study. Furthermore, pH in the upper GI tract of young, healthy subjects appears to be independent of gender. The differences in upper GI pH between the fasted and the fed state are discussed in terms of dosage form performance and absorption for orally administered drugs.

Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women.

Gastric and duodenal pH levels were measured in 79 healthy, elderly men and women (mean ± SD = 71 ± 5 years) under both fasted and fed conditions using the Heidelberg capsule technique. The pH was recorded for 1 hr in the fasted state, a standard liquid and solid meal of 1000 cal was given over 30 min, then the pH was measured for 4 hr postprandially. Results are given as medians and interquartile ranges: fasted gastric pH, 1.3 (1.1–1.6); gastric pH during the meal, 4.9 (3.9–5.5); fasted duodenal pH, 6.5 (6.2–6.7); and duodenal pH during the meal, 6.5 (6.4–6.7). Although fasted gastric pH, fasted duodenal pH, and duodenal pH during the meal differ statistically from those observed in young subjects, the differences are not expected to be clinically significant in terms of drug absorption for the majority of elderly subjects. Following a meal, gastric pH decreased from a peak pH of 6.2 (5.8–6.7) to pH 2.0 within 4 hr in most subjects. This rate of return was considerably slower than in young, healthy subjects. Nine subjects (11%) had a median fasted gastric pH >5.0, and in five of these subjects the median pH remained >5.0 postprandially. In this group, drugs and dosage forms which require an acidic environment for dissolution or release may be poorly assimilated.

Comparison of Gastrointestinal pH in Cystic Fibrosis and Healthy Subjects

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater gastric acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects,P<0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.

pH-Related Changes in the Absorption of Dipyridamole in the Elderly

The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (≥65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HC1 (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of 99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased Cmax and AUC(0–36) exhibited in achlorhydric subjects without pretreatment. Tmax and ka were slower in achlorhydrics, although pretreatment with glutamic acid HC1 tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to >5 in all subjects and maintained it at >5 for at least 3 hr in all subjects tested. The lack of differences in Cmax and AUC(0–36) with significant differences in Tmax and ka indicated that control subjects after treatment with famotidine may serve as an adequate model for achlorhydrics with respect to the extent of absorption, but not with respect to the rate of absorption. Gastric emptying of a nutrient liquid was significantly slower in achlorhydric subjects than in control subjects. Finally, fasting serum gastrin appeared to be a relatively reliable and easy method for screening for achlorhydria in the elderly.

Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers

BACKGROUND Zinc is an important nutrient and is necessary to maintain a multitude of physiologic processes. Mineral supplements that provide physiologic doses of zinc may be used when dietary zinc is inadequate. Zinc is also used in pharmacologic doses to treat zinc deficiency and diseases such as Wilsons disease and acrodermatitis enteropathica. Although there are several zinc salts available, they are not equal in solubility, which is thought to be a key factor in zinc absorption. Moreover, the solubility of the salts is affected by pH, which may vary between pH 1 and 7 under various physiologic conditions in the stomach. The objectives of this 2-way 4-phase crossover study were to evaluate the effect of high (> or = 5) and low (< or = 3) intragastric pH on the absorption of zinc from the acetate and oxide salt in young healthy volunteers. METHODS After a 9-hour fast, 10 healthy subjects (5 males and 5 females) were given a single oral dose of 50 mg of elemental zinc as the acetate or the oxide salt and under either high or low intragastric pH conditions. In all phases, a Heidelberg capsule pH detector-transmitter was used to continuously monitor intragastric pH. During the high pH phases, single oral doses of famotidine 40 mg oral suspension were administered before the zinc to raise the intragastric pH above 5. Intragastric pH < or = 3 was maintained in the low pH phases. RESULTS The mean plasma zinc area under the curve for zinc acetate at low pH (AL), zinc acetate at high pH (AH), zinc oxide at low pH (OL), and zinc oxide at high pH (OH) were 524, 378, 364, and 66 micrograms x h/dL, respectively. The highest zinc plasma concentrations occurred with the acetate salt at a low intragastric pH, while the lowest plasma concentrations occurred with the oxide salt at a high intragastric pH. The importance of pH to the dissolution of these salts was verified by in vitro tests. Twenty-four-hour urinary zinc excretion was the highest for the AL phase and lowest for the OH phase. CONCLUSION This study indicates that intragastric pH and salt solubility-dissolution are important in the oral absorption of zinc. Specifically, the oxide salt is not an appropriate zinc salt to use in those patients with elevated intragastric pH.

Stereoselective, Competitive, and Nonlinear Plasma Protein Binding of Ibuprofen Enantiomers as Determined in Vivo in Healthy Subjects

The plasma protein binding and competitive inhibition parameters of R(−)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4×4 Latin square design in which oral solutions of drug were administered as 300 mg R (−)-ibuprofen, 300 mg S (+)-ibuprofen, 300 mg R (−)-+300 mg S (+)-ibuprofen, and 300 mg R(−)-+600 mg S (+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled14C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was Stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2=0.358±0.185 vs. SP2=0.979 ±0.501 μg/ml; X±SD) but no differences in their binding capacity (RP1=160±86 vs. SP1=161 ±63 μg/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI=0.661 ±0.363 vs. RKI=0.436 ±0.210 μg/ml). As a result, the intrinsic binding (i.e.), P1/P2J of R(−)-ibuprofen was greater than S(±)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.

Absorption of Flurbiprofen in the Fed and Fasted States

The oral absorption of flurbiprofen, an antiinflammatory nonsteroidal compound, was compared in the fasted vs the fed state. When ingested as an aqueous solution of the sodium salt, absorption kinetics followed a monoexponential pattern in half of the subjects and a bimodal pattern with a lag time before the onset of the second phase of absorption in the other half of the subjects. When ingested in the free acid form as a tablet either with water (fasted state) or with water 15 min after 330 ml of apple juice (fed state), flurbiprofen absorption was always bimodal, and the lag time before the onset of the second phase was shown to be dependent on the gastric emptying time (r = 0.623, P < 0.01). The gastric emptying times were significantly longer when the drug was administered in the fed state (average GET = 57 min in the fasted state and 102 min in the fed state; P < 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.

Cyclosporine for Severe Ulcerative Colitis

Objective: To evaluate evidence for the use of cyclosporine in treating patients with severe ulcerative colitis. Data Sources: A literature search was performed using MEDLINE, EMBASE, Cochrane Database, and ISI Web of Knowledge (1966–November 2005) with the search terms cyclosporine, cyclosporin A, CsA, ulcerative colitis, UC, inflammatory bowel disease, IBD, steroid-refractory, and immunosuppression. Additional papers were located by hand-searching relevant references. Only human studies in adults and literature published in English were included. Data Synthesis: Intravenous cyclosporine has been evaluated for the treatment of severe ulcerative colitis in 4 randomized, controlled trials, as well as in many open-label and retrospective studies. Studies that evaluated cyclosporine for severe ulcerative colitis were reviewed. All 4 controlled trials showed an initial positive clinical response as defined by the Crohns Activity Index when intravenous cyclosporine 4 mg/kg/day was administered as monotherapy or combined with intravenous corticosteroids. One of the 4 trials indicated that high-dose cyclosporine (4 mg/kg/day) has no additional clinical benefit over the low-dose (2 mg/kg/day) and that the lower dose may improve safety related to dose-dependent adverse effects. Conclusions: There is evidence to support the use of intravenous cyclosporine for patients with severe ulcerative colitis who are refractory to corticosteroid therapy. Because most of the adverse effects associated with cyclosporine are dose dependent, therapy should be initiated with the lower 2 mg/kg/day dose. Subsequent doses should be adjusted based on cyclosporine blood concentrations of 150–250 ng/mL. Cyclosporine should be used only to induce remission and serve as a “bridge” to azathioprine or 6-mercaptopurine maintenance therapy. At this time, there are insufficient data to support the long-term use of cyclosporine monotherapy for avoidance of surgery or maintenance of remission.

High viscosity hydroxypropylmethylcellulose reduces postprandial blood glucose concentrations in NIDDM patients

The ability of high viscosity hydroxypropylmethylcellulose (HPMC) to reduce postprandial glucose concentrations was assessed in patients with non-insulin-dependent diabetes (NIDDM) and healthy volunteers. The study design consisted of a two-way crossover, single-dose administration of 10 g prehydrated high viscosity HPMC, or placebo, with a standard carbohydrate-rich meal. In patients with NIDDM, HPMC reduced blood glucose concentrations at the 60-, 75-, 90-, 120- and 150-min sampling intervals, with an average reduction in the maximum postprandial blood glucose concentration, Cmax, of 24% (P < 0.05). The time at which the maximum concentration was reached, Tmax, remained unchanged. The area under the blood concentration versus time plot, AUC0-6h, was reduced by an average of 15% (P < 0.05). The blood concentration profile of insulin followed that of glucose. Concentrations were significantly lower than in the placebo phase only at the 120-min sampling time, while pharmacokinetic parameters (Cmax, Tmax and AUC0-6h) were unchanged. These results suggest that alterations in the blood glucose profile are mediated by luminal events rather than by changes in hormonal response. In contrast to the NIDDM patients, neither the pharmacokinetic parameters nor the blood glucose concentrations at specific sampling times were significantly affected by the co-administration of HPMC in healthy volunteers. Overall, the results of this study suggest that HPMC may be a useful adjunct in the management of NIDDM.

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with chronic renal failure

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five‐ to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P < 0.05), nonrenal clearance vs. percent free (r = 0.796; P < 0.01), and renal clearance vs. creatinine clearance (r = 0.995; P < 0.001). Although bioavailability was relatively consistent among the HS (0.664 ± 0.112) and CRF (0.689 ± 0.149) groups, the absorption‐time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group.