and Ketoconazole - Antimicrobial Agents and Chemotherapy

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Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole. ("100%o) in solution. In contrast, significant ...

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1994, p. 319-325

Vol. 38, No. 2

0066-4804/94/$04.00+0 Copyright (C 1994, American Society for Microbiology

In Vitro Analysis of the Interaction between Sucralfate and Ketoconazole JAMES D.

HOESCHELE,1 ANINDYA K. ROY,' VINCENT L. PECORARO,' AND PEGGY L. CARVER2* The Department of Chemistry' and the College of Pharmacy, 2 The University of Michigan, Ann Arbor, Michigan 48109-1065

Received 9 November 1993/Returned for modification 21 February 1993/Accepted 30 November 1993

In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole ("100%o) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, -35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)2+, H(ketoconazole)+, or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)2+ or H(ketoconazole)+ forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.

Ketoconazole is a dibasic imidazole antifungal agent with a of 6.51 and a PKa2 of 2.94 that is virtually insoluble in neutral or slightly acidic solutions (3, 13). Recent studies have demonstrated that the dissolution and subsequent absorption of ketoconazole in humans are dependent on the presence of low gastric pH (1, 3, 8, 11). Sucralfate is a basic aluminum salt of sucrose octasulfate that forms aluminum ions and sucrose sulfate anions in solution at low pHs (14). Preliminary in vitro studies in our laboratory demonstrated that the addition of sucralfate to 50-ml aqueous solutions of ketoconazole at pH 1 or 2 results in a significant decrease in the amount of ketoconazole in solution. In a subsequent study with healthy volunteers (4), we demonstrated that the oral bioavailability of ketoconazole was significantly decreased during simultaneous administration with sucralfate. We hypothesized that sucralfate may interact with ketoconazole by adsorption of ketoconazole to the paste form of sucralfate (produced at low pH) by an electrostatic interaction between the mono- or divalently charged ketoconazole moieties and the negatively charged sucrose octasulfate ions or by some combination of these two factors. However, since sucralfate acts as a buffer with a pK. of approximately 4.5 (9, 14), a decrease in ketoconazole concentrations in solutions with an

initial pH of 93% soluble in 100-ml SGF solutions maintained at pHs of 1 (99%), 2 (100%), 3 (93%), and 4 (94%). At pH 6, a milky precipitate formed, which, after filtration, yielded only 5% of the maximal available ketoconazole concentration in solution. Therefore, in the range of pHs 1 to 4, ketoconazole is completely soluble in 100 ml of SGF. AK As expected, the addition of GA to SGF leads to an increase in solution acidity. The effect is minor at an initial pH of 1; however, it is marked at higher pHs. Equilibrium pH is rapidly achieved regardless of initial pH. Most important, the addition of GA ensures that the final solution pH will remain below 2 regardless of the initial solution acidity. Regardless of the initial pH, AK solutions showed the same high level of ketoconazole ('100%) in solution (Fig. 4). As seen in Table 2, the soluble ketoconazole levels in SGF do not directly correlate with any of the predicted distributions of individual protonation forms of ketoconazole. SK. The most dramatic changes in pH were observed following the addition of both sucralfate and ketoconazole to SGF solutions. The pHs of SGF solutions at initial pHs of 1, 2, and 3 are markedly increased by the addition of sucralfate. After only 30 min, a pH 1 starting solution is raised to pH 1.8 and after 2 h has equilibrated at pH 2.7. Similarly, solutions with initial pHs of 2 and 3 exhibit final (2-h) pHs of 4.2 and 4.35, respectively. Most interesting is the observation that addition of sucralfate to SGF at pH 6 results in an increased acidity as the pH drops to 5. This is consistent with our observation that sucralfate effectively buffers solutions to a pH of -4. Appreciable decreases in the soluble ketoconazole levels were observed when sucralfate was mixed with ketoconazole.

322

ANTIMICROB. AGENTS CHEMOTHER.

HOESCHELE ET AL.

A

7a-

6-

U

0 C C

0

'i

a 3 3

0 co

2-

U

0

0

0

0

A

A

2

3

0

S

S

A

1

1-

0

1

4

5

6

7 Initial pH

FIG. 4. Comparison of the observed ketoconazole concentrations (K%) in AK, SK, and ASK 30 min and 2 h after addition of drug to SGF. The concentrations were measured at the equilibrium (final) pH of each solution. *, K% in AK after 30 min; E, K% in SK after 30 min; 1,K% in ASK after 30 min; El, K% in AK after 2 h; l, K% in SK after 2 h; P, K%o in ASK after 2 h. Final pHs are given in Table 2.

Initial pH

B 1.0

0.8

I

I I I I I I I

0.6 I

A pH

I

0.4

0.2'

I

-0.2 1

2

3

6

Initlal pH FIG. 3. The pH dependence of drug dissolution in SGF. (A) pH 30 min (open symbols) and 2 h (solid symbols) after addition of drug. A, A, AK; 0, 0, ASK; [, *, SK. (B) Difference between pHs at 30 min and 2 h after addition of drug. M, AK; 1, ASK; E, SK.

As little as 14% of the ketoconazole originally added to SGF remains in a soluble fraction 2 h after the addition of sucralfate, despite the fact that the solution is still rather acidic (pH 2.72). In comparison, 96% of the available ketoconazole was soluble at pH 2.72 in the absence of sucralfate. Most interesting, at pHs between 4 and 5, there was no detectable ketoconazole in solution, despite the fact that ketoconazole alone is still soluble in SGF at this pH (Table 2). As shown in Fig. 4, longer exposure times led to lower ketoconazole concentrations. For example, at an initial pH of 1, SK solutions at 30 min versus those at 2 h yield K%s of 23 versus 14, respectively. Although the pH of the SK solutions continued to rise between 30 min and 2 h, the increased basicity was not the sole cause of the lowered ketoconazole solubilities. This is clearly seen by comparing the K%s for SK at pH 1 (pH = 1.78, K% = 23) and SK at pH 2 (pH = 4.00, K%o = 23) at 30 min. Furthermore, there is no correlation between the predicted ratios of H2(ketoconazole)2+, H(ketoconazole)+, or ketoconazole and the observed ketoconazole solubilities. ASK. As shown in Fig. 3, there is a net decrease in acidity from the initial values for the pH 1, 2, and 3 ASK solutions. The effect is minor, however, since the largest difference between AK and ASK for these three solutions is 0.6 pH units. However, once again, the pH 6 solution becomes markedly more acidic. The bottom graph of Fig. 3 illustrates that the

ASK solutions undergo the slowest approach to pH equilibrium. In general, the pHs of the ASK solutions increased by 0.4 pH units between 30 and 120 min. The addition of GA to SK leads to a significant increase in the concentration of solubilized ketoconazole, especially for solutions with initial pHs of 3 or greater (Fig. 4). For example, after 30 min, there is no detectable ketoconazole in SK at an initial pH of 3 or 6 (Table 2), while 46 to 60% of ketoconazole is still soluble in ASK solutions at an initial pH of 3 or 6. However, even with an initial pH of SGF at 1 or 2, the soluble ketoconazole concentrations nearly double in the presence of GA. Like those in SK solutions, ketoconazole concentrations in ASK solutions decreased substantially between 30 min and 2 h. Only at an initial pH of 1 was the ketoconazole concentration invariant between these two time points. The greatest effect was at an initial pH of 6, where the ketoconazole concentration dropped from 60% to 36%. There is a slight, but potentially important, difference in pH between the 30-min and 2-h ASK samples (Fig. 3). Utilizing data in Table 2, one can compare the observed ketoconazole concentrations with the predicted ketoconazole solubilities, assuming that the soluble form of the drug is H2(ketoconazole)2+, H(ketoconazole), or both species. Clearly there is no direct correlation between the protonation states of ketoconazole and the amount of soluble ketoconazole in SGF, demonstrating that a change in pH due to the addition of sucralfate is not the mechanism of drug interaction. The data presented in Fig. 4 represent the ketoconazole solubility that one would expect when utilizing various drug combinations in patients with gastric pHs ranging between 1 and 6. However, this analysis does not distinguish pH effects that may be important for direct chemical interaction between ketoconazole and sucralfate (e.g., the protonation state of sucralfate varies through the pH range of 2 to 5, and the different forms of sucralfate could interact with ketoconazole differently). Furthermore, it does not identify the role other than alteration of pH that GA may play in enhancing the solubility of ketoconazole. The data in Table 2 demonstrate that ketoconazole is, as expected, essentially 100% available in the AK solutions. The addition of acid to SK solutions causes a dramatic increase in the solubility of ketoconazole, especially at the high pHs; the addition of acid to SK at pHs of 3 and 6 increased ketocon-

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TABLE 2. Ketoconazole concentrations in SGF 30 min and 2 h after addition of ketoconazole pH

K%C

Solution

K

Cadj

Initiala

Finalb

30 min postaddition AK AK AK AK SK SK SK SK ASK ASK ASK ASK

1 2 3 6 1 2 3 6 1 2 3 6

0.98 1.71 1.90 1.93 1.78 4.00 4.32 4.89 1.41 2.29 2.32 2.28

104 103 98 99 23 23 0 0 37 52 46 60

96 95 100 102 25

2 h postaddition AK AK AK AK SK SK SK SK ASK ASK ASK ASK

1 2 3 6 1 2 3 6 1 2 3 6

0.93 1.70 1.87 1.93 2.72 4.07 4.35 4.89 2.08 2.72 2.67 2.70

101 99 102 102 14 20 0 0 35 37 37 36

96 96 100 98 18 49 33 34

44 48 34

KH2K

K

KK

98.9 94.4 91.6 91.1 93.5 8.0 4.0 1.1 97.1 81.7 80.7 82.0

1.1 5.6 8.4 8.9 6.5 91.7 95.4 96.7 2.9 18.3 19.3 18.0

0.0 0.0 0.0 0.0 0.0 0.3 0.6 2.3 0.0 0.0 0.0 0.0

99.0 94.6 92.2 91.1 62.4 6.9 3.7 1.1 87.9 62.4 65.1 63.5

1.0 5.4 7.8 8.9 37.6 92.8 95.6 96.7 12.1 37.6 34.9 36.5

0.0 0.0 0.0 0.0 0.0 0.3 0.6 2.3 0.0 0.0 0.0 0.0

a Initial pH of solution at the start of the experiment. b Final pH (2 h after the start of the experiment). C K%, ratio of observed to maximal ketoconazole concentration in SGF (equation 1) at 30 min or 2 h (prior to adjustment to final pH of ASK experiment); K%adj, ratio of observed to maximal ketoconazole concentration in SGF after adjustment to the final pH of the ASK experiment with the corresponding initial pH. d Predicted (equations 5 to 7) percentage of concentration of H2(ketoconazole)2+ (KH2K), H(ketoconazole)+ (KHK), and ketoconazole (KK) at the final pH of the

experiment.

azole concentrations from 0 to 48% and from 0 to 34%, respectively. In fact, at these high pHs, the concentrations of ketoconazole in ASK and pH-adjusted SK samples are comparable. It appears that pH can influence ketoconazole solubility, even though there is no direct correlation between the protonation state of ketoconazole and the amount of soluble ketoconazole present in SGF. We can also conclude that it is the presence of the protons and not the glutamic acid that is the important factor in increasing ketoconazole concentrations in the ASK samples. DISCUSSION The rationale for the specific study design of this in vitro analysis was the methodology employed in our previous study with human subjects that demonstrated a decreased bioavailability of ketoconazole during simultaneous administration with sucralfate. In this study, subjects were administered two oral 680-mg doses of GA 10 min apart. A 400-mg oral dose of ketoconazole (with or without a 1-g oral dose of sucralfate) was administered with the second dose of GA. Simultaneous administration with sucralfate resulted in a 24% decrease in the bioavailability of ketoconazole (4). We sought to mimic the clinical conditions in vitro in order to understand the interaction of sucralfate and ketoconazole on the molecular level. Our hypothesis was that ketoconazole and sucralfate undergo an electrostatic interaction, significantly decreasing the amount of ketoconazole available for transport across the gastrointestinal epithelium.

Ketoconazole has a pKai of 6.51 and a pKa2 of 2.94 and is virtually insoluble in neutral or slightly acidic solutions (3). However, Carlson et al. (3) reported that the in vitro dissolution of ketoconazole was rapid and virtually complete (>90%) in buffer solutions at pHs of 2, 3, and 4. At pH 5, only 37% of ketoconazole was in solution, while only 10% was available at pH 6. In contrast, we found that dissolution of ketoconazole was strongly dependent on the pH, medium, and (at pH 3) the volume of solution. Regardless of the volume studied, dissolution of ketoconazole in aqueous solutions at pH 3 was poor. In 100 ml of SGF, ketoconazole was >93% soluble in the pH range of 1 to 4. Since unbuffered solutions were utilized, the differences in ketoconazole solubility in aqueous solutions at pH 3 for 50 versus 500 ml are not surprising. As a weak base, the addition of ketoconazole increases pH; this effect is more pronounced in smaller fluid volumes. Because sucralfate and ketoconazole are weak bases and GA is a moderately strong acid, all three drugs can perturb gastric pH. Although the shift in pH is less in SGF than in water because pepsin and other proteins can act as buffers, marked pH changes can still be observed. In particular, sucralfate, which buffers solutions towards a pH of -4.5, dramatically increases the pH of 100-ml SGF solutions at initial pHs of less than 3 and decreases the pH of solutions that are initially at pH 6 (Table 2). Ketoconazole produces only minor effects on the pH of SGF (less than half a log unit). Addition of GA leads to very acidic solutions (pH c2) regardless of the initial pH of the SGF. Most important for

ANTIMICROB. AGENTS CHEMOTHER.

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324

X

50 100-

40-

60 0X60 40-

W

o

20

0.1^. 0

I

2

3

6

2

3

'l-

6

Initial pH

Initial pH FIG. 5. Comparison of the observed ketoconazole concentrations in AK, SK, and ASK 30 min and 2 h after addition of drug to SGF. The concentrations were measured after the AK and SK solutions had been adjusted to the same pH (K%adj) as the final pH for the ASK sample that had the identical initial pH value. *, K%adj in AK after 30 min; E, K%adj in SK after 30 min; El, K%adj in ASK after 30 min; El, K%adj in AK after 2 h; El, K%adj in SK after 2 h; E, K%adj in ASK after 2 h. Adjusted pHs are given in Table 2 in the rows for ASK entries.

clinical studies, the addition of GA to an SK mixture leads to a constant final pH (-2.7) for gastric pHs that initially ranged between 2 and 6. This supports the findings of our previous study of healthy subjects with elevated gastric pH following administration of a 300-mg oral dose of ranitidine, in whom administration of two 680-mg oral doses of GA decreased median gastric pH from 6.2 to 1.6 within 15 min (7). Decreased in vitro solubility of ketoconazole may result from an increase in solution pH following the addition of sucralfate. We evaluated this possibility in two ways. First, we examined the solubility of ketoconazole alone in SGF in the pH range of 1 to 6. We observed that ketoconazole was soluble in SGF at pHs of less than 6. This indicates that if the mechanism of the ketoconazole-sucralfate interaction is mediated solely by an increase in solution pH, then addition of sucralfate would require that the pH of the solution be increased to greater than 5. As shown in Table 2, although no sucralfate-containing solution has a pH greater than 5, all have dramatically decreased ketoconazole levels. Second, we have calculated the concentrations of H2(ketoconazole), H(ketoconazole), and ketoconazole by using the literature values for the acid dissociation constants and have shown that there is no correlation between any of the predicted concentrations of protonation forms and the observed solubility of drug in SGF. This is in contrast to our findings for unbuffered aqueous solutions or to those of Carlson et al. (3) for buffered solutions. These findings lead us to reject simple pH elevation as the mechanism of interaction between ketoconazole and sucralfate in SGF or in human subjects. Furthermore, our studies indicate that both H2(ketoconazole)2' and H(ketoconazole)+ are soluble in SGF. They also suggest that the impaired absorption of ketoconazole observed clinically in subjects with a gastric pH of >3 (2, 8) may reflect binding or complexation of ketoconazole with pepsin present in gastric fluid. Although drug remains soluble, it is unavailable for transport across the gastrointestinal epithelium. The addition of GA and sucralfate to a solution of ketoconazole in SGF results in a profound increase in soluble ketoconazole concentrations. Since H(ketoconazole)+ is far more

FIG. 6. Comparison of the observed difference in ketoconazole concentrations in AK and SK solutions before (K%) and after (K%adj) adjustment to the same pH as the final pH for the ASK sample that had the identical initial pH value. The pHs prior to adjustment are given for each sample in Table 2 in the final pH column. The adjusted pHs are given in Table 2 in the rows for ASK entries. For example, after 2 h, SK at an initial pH of 6 had a final pH of 4.89. The pH of the SK solution was adjusted to 2.70, the value for ASK with an initial pH of 6 after 2 h. K%adj - K% (34 - 0) = 34. *, K%adj -K% for AK after 30 min; z, K%adj - K% for SK after 30 min; C, K%adj - KNo for AK after 2 h; 1, K%adj - K% for SK after 2 h.

soluble than H2(ketoconazole)2+, this finding suggests two disparate roles for GA. At pH 4, '40% of GA is present as the glutamate monoanion. The monoanion may compete with the sucralfate polymer for H2(ketoconazole)2+ or H(ketoconazole)+ via an electrostatic interaction. Alternatively, the glutamic acid portion of GA may be irrelevant and the role of GA may be simply as an acid. For example, it is possible that sucralfate protonation states differ in their ability to interact with ketoconazole. Therefore, one would observe a pH dependence for the interaction, but this dependence would not correlate directly with ketoconazole protonation species. In order to differentiate these two possibilities, we compared the solubilities of ketoconazole in a variety of pH-adjusted sucralfate mixtures (Fig. 5 and 6). With the exception of SGF samples with an initial pH of 1, the amounts of soluble ketoconazole in the presence and absence of GA were equivalent (within experimental error). At pH 1, the observed deviation is likely due to development of a different polymeric form of sucralfate. The gelatinous, intractable polymer of sucralfate that develops at pH 1 may trap ketoconazole within its matrix during the mixing process. The polymer precipitates with ketoconazole, making it kinetically inaccessible to further reactions with sucralfate. These data strongly suggest that the role of GA is not to interact directly with ketoconazole and are most reasonably attributed to the decreasing pH of the gastric fluid. The pH effects are probably the result of changes in the protonation states of sucralfate and/or the release of A12(OH)5+ from sucralfate as the solution becomes more acidic. If so, one would expect the increase in ketoconazole concentrations observed when SK solutions are adjusted to ASK pHs to show a bell-shaped curve peaking around pH 4.5, the pK of sucralfate. This exact trend is observed in Fig. 5. Similar trends have been observed by Hikal and colleagues (6), who reported maximal adsorption of furosemide (a weak base) at pH 3 (initial pH), and by Nagashima (9, 10), who found a similar trend with bile acids. Therefore, the pH dependence of

VOL. 38, 1994

IN VITRO INTERACTION OF SUCRALFATE WITH KETOCONAZOLE

the ketoconazole-sucralfate interaction is likely to be a consequence of the weak acidity of the sucralfate molecule. Although GA enhances the solubility of ketoconazole in the presence of sucralfate, it does not completely remove the interaction. In fact, despite the addition of GA, only -38% of the added ketoconazole is soluble after 2 h in the presence of sucralfate. Interestingly, these findings suggest that if GA had not been utilized in the previous pharmacokinetic study (4), an even more dramatic interaction between ketoconazole and sucralfate might have been observed because of the elevation of gastric pH from sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)2+ or H(ketoconazole)+ forming an electrostatic interaction with the sucralfate polyanion. If ketoconazole species form ion pairs with the highly insoluble sucralfate polymer, ketoconazole would be unavailable for transport across the gut epithelium. As the pH of gastric fluid is decreased, sucralfate interacts differently with the ketoconazole, and the antifungal agent becomes slightly more soluble. The findings of this study suggest that the interaction of sucralfate with ketoconazole and other weak bases is pH dependent and that maximal interaction occurs when the final pH of the solution is approximately 4. We conclude that the significant decrease in ketoconazole concentrations associated with sucralfate administration is not simply the result of perturbed gastric acidity and must result from a direct chemical interaction. These data suggest that other azole antifungal agents may interact with sucralfate via a similar mechanism. REFERENCES 1. Andrews, F. A., L. R. Peterson, W. H. Beggs, D. Crankshaw, and G. A. Sarosi. 1981. Liquid chromatographic assay of ketoconazole. Antimicrob. Agents Chemother. 19:110-113. 2. Blum, R. A., D. T. D'Andrea, B. M. Florentino, J. H. Wilton, D. M. Hilligoss, M. J. Gardner, E. B. Henry, H. Goldstein, and J. J.

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Schentag. 1991. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann. Intern. Med. 114:755-757. Carlson, J. A., H. A. Mann, and D. M. Canafax. 1983. Effect of pH on disintegration and dissolution of ketoconazole tablets. Am. J. Hosp. Pharm. 40:1334-1336. Carver, P. L., R. R. Berardi, M. J. Knapp, J. M. Rider, C. A. Kauffman, S. F. Bradley, and M. Atassi. 1994. In vivo interaction of ketoconazole and sucralfate in healthy volunteers. Antimicrob. Agents Chemother. 38:326-329. Fasman, G. D. (ed.). 1973. Handbook of biochemistry and molecular biology: physical and chemical data section, 3rd ed., p. 354. CRC Press, Inc., Boca Raton, Fla. Hikal, A. H., L. A. Walker, and T. Ramachandran. 1987. In vitro and in vivo interactions of furosemide and sucralfate. Pharm. Res. 4:171-172. Knapp, M. J., R. R. Berardi, J. B. Dressman, J. M. Rider, and P. L. Carver. 1991. Modification of gastric pH with oral glutamic acid hydrochloride. Clin. Pharm. 10:866-869. Lelawongs, P., J. A. Barone, J. L. Colaizzi, A. T. Hsuan, W. Mechlinski, R. Legendre, and J. Guarnieri. 1988. Effect of food and gastric acidity on absorption of orally administered ketoconazole. Clin. Pharm. 7:228-235. Nagashima, R. 1981. Development and characteristics of sucralfate. J. Clin. Gastroenterol. 3(Suppl. 2):103-110. Nagashima, R., and N. Yoshida. 1979. Sucralfate, a basic aluminum salt of sucrose sulfate. Arzneim.-Forsch. 29:1668-1676. Piscitelli, S. C., T. F. Goss, J. H. Wilton, D. T. D'Andrea, H. Goldstein, and J. J. Schentag. 1991. Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob. Agents Chemother. 35:1765-1771. U.S. Pharmacopoeial Convention Inc. 1985. USP XXI-NFXVI, p. 1424. U.S. Pharmacopoeial Convention Inc., Rockville, Md. Van Tyle, H. J. 1984. Ketoconazole: mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 4:343-373. Yoshida, N., N. Terao, and R. Nagashima. 1980. Sucralfate, a basic aluminum salt of sucrose sulfate. IV. Interaction with enzyme pepsin. Arzneim.-Forsch. 30:79-80.

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