Br. J. clin. Pharmac. (1990), 29
Letter to the Editors
783
Diseases and drugs but not food decrease ketoconazole 'bioavailability' Winstanley & Orme (1989) include ketoconazole as an antimicrobial agent whose bioavailability is reduced by food. Apart from one study (Mannisto et al., 1982) other evidence suggests the opposite. After a 200 mg dose given to 30 patients with onychomycosis, Gascoigne et al. (1981) found higher and more consistent ketoconazole concentrations 1 and 2 h post-dose when the drug was taken during a standard breakfast. In another study in eight volunteers given ketoconazole in the fasting state and also with a standard breakfast, there was no evidence of a food-associated impairment in absorption (Daneshmend et al., 1984a,b). This study found consistently higher AUCs when ketoconazole was taken with a standard breakfast at doses of 200 mg, 400 mg, 600 mg and 800 mg. The mechanism by which food increases ketoconazole AUC remains unclear. In the absence of an intravenous formulation, the absolute bioavailability of ketoconazole in man is not known. Ketoconazole is a relatively insoluble drug: a weak dibasic compound (pKa1 = 6.51; pKa2 = 2.94) and almost insoluble in water except at a pH lower than 3. Ketoconazole tablet dissolution (but not disintegration) is pHdependent in vitro (Carlson etal., 1983). At pH 2 and 3, dissolution of ketoconazole is rapid (more than 85% in 5 min and complete after 30 min). In contrast, at pH 6 only 10% of ketoconazole is in solution after 1 h. When the pH of the solution exceeds 5.5, ketoconazole precipitates (Carlson et al., 1983). Consequently, its absorption would be expected to be influenced by factors affecting gastric acidity. The effects of food on gastric acidity (or pH) are complex. The immediate effect of food is to buffer gastric acidity, but it is also a potent stimulus for acid secretion. This may explain the food-associated prolongation in
ketoconazole tmax accompanying the increase in AUC. The importance of gastric acid in ketoconazole absorption is confirmed by the reduction in mean peak concentrations and AUC following co-administration with cimetidine (van der Meer et al., 1980) and antacid (Brass et al., 1982). However attempts to enhance ketoconazole absorption by incorporating acidic compounds into the formulation or giving exogenous acid have been generally unsuccessful (Daneshmend et al., 1986; Sutherland et al., 1983). Ketoconazole absorption is reduced in patients with chronic renal failure (Chapman & Warnock, 1982), in bone marrow transplant recipients (Hann et al., 1982), in patients with haematological malignancy receiving anti-tumour chemotherapy (Stockley et al.. 1986; Vu Van et al., 1983) and this may relate to the phase of neutropenia (Donnelly et al., 1984). More recently, it has been shown that the hypochlorhydria found in patients with AIDS impairs ketoconazole absorption and this can be corrected by coadministration of the drug with 200 ml of O. N hydrochloric acid (Lake-Bakaar et al. 1988a,b). In summary, present evidence suggests that ketoconazole absorption is generally improved by food, but reduced by certain diseases and drugs that reduce gastric acid. T. K. DANESHMEND Department of Medicine, Royal Devon and Exeter Hospital (Wonford), Barrack Road, Exeter EX2 SDW
Received 31 January 1990, accepted 5 February 1990
References Brass, C., Galgiani, J. N., Blaschke, T. F., Defelice, R., O'Reilly, R. A. & Stevens, D. A. (1982). Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob. Agents Chemother., 27, 151158. Carlson, J. A., Mann, H. J. & Canafax, D. D. (1983). Effect of pH on disintegration and dissolution of ketoconazole tablets. Am. J. Hosp. Pharm., 40,
1334-1336.
Chapman, J. R. & Warnock, D. W. (1983). Ketoconazole and fungal CAPD peritonitis. Lancet, ii, 510-511. Daneshmend, T. K., Mason, A. R., Lowe, C. H., Warnock, D. W. & Johnson, E. M. (1986). Influence of formulation on ketoconazole pharmacokinetics in man: comparison of standard tablet vs capsule containing citric acid. J. Antimicrob. Chemother., 18, 289-291.
784
Letter to the Editors
Daneshmend, T. K., Warnock, D. W., Ene, M. D., Johnson, E. M., Potten, M. R., Richardson, M. D. & Williamson, P. J. (1984a). Absence of a food associated reduction in ketoconazole absorption at 200, 400, 600 and 800 mg doses in man. Br. J. clin. Pharmac., 17, 197P. Daneshmend, T. K., Warnock, D. W., Ene, M. D., Johnson, E. M., Potten, M. R., Richardson, M. D. & Williamson, P. J. (1984b). Influence of food on the pharmacokinetics of ketoconazole. Antimicrob. Agents Chemother., 25, 1-3. Donnelly, J. P., Starke, I. D., Galton, D. A. G., Catovsky, D., Goldman, J. M. & Darrell, J. H. (1984). Oral ketoconazole and amphotericin B for prevention of yeast colonization in patients with acute leukaemia. J. Hosp. Infect., 5, 83-93. Gascoigne, E. W., Barton, G. J., Michaels, M., Meuldermans, W. & Heykants, J. (1981). The kinetics of ketoconazole in animals and man. Clin. Res. Rev., 1, 177-187. Hann, I. M., Prentice, H. G., Keaney, M., Corringham, R., Blacklock, H. A., Fox, J., Gascoigne, E. & van Cutsem, J. (1982). The pharmacokinetics of ketoconazole in severely immunocompromised patients. J. Antimicrob. Chemother., 10, 489-496. Lake-Bakaar, G., Cohen, P. & Strauss, E. W. (1988a). AIDS gastropathy: antibodies to gastric parietal cell. Gastroenterology, 94 (Part 2), A247. Lake-Bakaar, G., Tom, W., Gupta, N., Lake-Bakaar, D., Beidas, S., Elsakr, M. & Strauss, E. W.
(1988b). AIDS gastropathy: reversible ketoconazole malabsorption. Gastroenterology, 94 (Part 2), A247. Mannisto, P. T., Mantyla, R., Nykanen, S., Lamminsivu, U. & Ottoila, P. (1982). Impairing effect of food on ketoconazole absorption. Antimicrob. Agents Chemother., 21, 730-733. Stockley, R. J., Daneshmend, T. K., Bredow, M. T., Warnock, D. W., Richardson, M. D. & Slade, R. R. (1986). Ketoconazole pharmacokinetics during chronic dosing in adults with haematological malignancy. Eur. J. clin. Microbiol., 5, 513-517. Sutherland, C., Murphy, J. E. & Schleifer, N. H. (1983). The effects of two gastric acidifying agents on the pharmacokinetics of ketoconazole. Abstract. The American Society of Hospital Pharmacists. 18th Annual Midyear Clinical Meeting, Atlanta, Georgia, December 4-8. Van der Meer, J. W. M., Keuning, J. J., Scheijgrond, H. W., Heykants, J. & van Cutsem, J. (1980). Influence of gastric acidity on the bioavailability of ketoconazole. J. Antimicrob. Chemother., 6, 522524. Vu Van, H., Piens, M. A., Archimbaud, E., Monier, M. F., Goyotat, D., Mojon, M. & Fiere, D. (1983). Serum levels of ketoconazole in bone marrow transplanted patients. Nouvelle Revue Fran,aise d'Hematologie, 25, 241-244. Winstanley, P. A. & Orme, M. L'E. (1989). The effects of food on drug bioavailability. Br. J. clin. Pharmac., 28, 621-628.
Letter to the Editors
783
Diseases and drugs but not food decrease ketoconazole 'bioavailability' Winstanley & Orme (1989) include ketoconazole as an antimicrobial agent whose bioavailability is reduced by food. Apart from one study (Mannisto et al., 1982) other evidence suggests the opposite. After a 200 mg dose given to 30 patients with onychomycosis, Gascoigne et al. (1981) found higher and more consistent ketoconazole concentrations 1 and 2 h post-dose when the drug was taken during a standard breakfast. In another study in eight volunteers given ketoconazole in the fasting state and also with a standard breakfast, there was no evidence of a food-associated impairment in absorption (Daneshmend et al., 1984a,b). This study found consistently higher AUCs when ketoconazole was taken with a standard breakfast at doses of 200 mg, 400 mg, 600 mg and 800 mg. The mechanism by which food increases ketoconazole AUC remains unclear. In the absence of an intravenous formulation, the absolute bioavailability of ketoconazole in man is not known. Ketoconazole is a relatively insoluble drug: a weak dibasic compound (pKa1 = 6.51; pKa2 = 2.94) and almost insoluble in water except at a pH lower than 3. Ketoconazole tablet dissolution (but not disintegration) is pHdependent in vitro (Carlson etal., 1983). At pH 2 and 3, dissolution of ketoconazole is rapid (more than 85% in 5 min and complete after 30 min). In contrast, at pH 6 only 10% of ketoconazole is in solution after 1 h. When the pH of the solution exceeds 5.5, ketoconazole precipitates (Carlson et al., 1983). Consequently, its absorption would be expected to be influenced by factors affecting gastric acidity. The effects of food on gastric acidity (or pH) are complex. The immediate effect of food is to buffer gastric acidity, but it is also a potent stimulus for acid secretion. This may explain the food-associated prolongation in
ketoconazole tmax accompanying the increase in AUC. The importance of gastric acid in ketoconazole absorption is confirmed by the reduction in mean peak concentrations and AUC following co-administration with cimetidine (van der Meer et al., 1980) and antacid (Brass et al., 1982). However attempts to enhance ketoconazole absorption by incorporating acidic compounds into the formulation or giving exogenous acid have been generally unsuccessful (Daneshmend et al., 1986; Sutherland et al., 1983). Ketoconazole absorption is reduced in patients with chronic renal failure (Chapman & Warnock, 1982), in bone marrow transplant recipients (Hann et al., 1982), in patients with haematological malignancy receiving anti-tumour chemotherapy (Stockley et al.. 1986; Vu Van et al., 1983) and this may relate to the phase of neutropenia (Donnelly et al., 1984). More recently, it has been shown that the hypochlorhydria found in patients with AIDS impairs ketoconazole absorption and this can be corrected by coadministration of the drug with 200 ml of O. N hydrochloric acid (Lake-Bakaar et al. 1988a,b). In summary, present evidence suggests that ketoconazole absorption is generally improved by food, but reduced by certain diseases and drugs that reduce gastric acid. T. K. DANESHMEND Department of Medicine, Royal Devon and Exeter Hospital (Wonford), Barrack Road, Exeter EX2 SDW
Received 31 January 1990, accepted 5 February 1990
References Brass, C., Galgiani, J. N., Blaschke, T. F., Defelice, R., O'Reilly, R. A. & Stevens, D. A. (1982). Disposition of ketoconazole, an oral antifungal, in humans. Antimicrob. Agents Chemother., 27, 151158. Carlson, J. A., Mann, H. J. & Canafax, D. D. (1983). Effect of pH on disintegration and dissolution of ketoconazole tablets. Am. J. Hosp. Pharm., 40,
1334-1336.
Chapman, J. R. & Warnock, D. W. (1983). Ketoconazole and fungal CAPD peritonitis. Lancet, ii, 510-511. Daneshmend, T. K., Mason, A. R., Lowe, C. H., Warnock, D. W. & Johnson, E. M. (1986). Influence of formulation on ketoconazole pharmacokinetics in man: comparison of standard tablet vs capsule containing citric acid. J. Antimicrob. Chemother., 18, 289-291.
784
Letter to the Editors
Daneshmend, T. K., Warnock, D. W., Ene, M. D., Johnson, E. M., Potten, M. R., Richardson, M. D. & Williamson, P. J. (1984a). Absence of a food associated reduction in ketoconazole absorption at 200, 400, 600 and 800 mg doses in man. Br. J. clin. Pharmac., 17, 197P. Daneshmend, T. K., Warnock, D. W., Ene, M. D., Johnson, E. M., Potten, M. R., Richardson, M. D. & Williamson, P. J. (1984b). Influence of food on the pharmacokinetics of ketoconazole. Antimicrob. Agents Chemother., 25, 1-3. Donnelly, J. P., Starke, I. D., Galton, D. A. G., Catovsky, D., Goldman, J. M. & Darrell, J. H. (1984). Oral ketoconazole and amphotericin B for prevention of yeast colonization in patients with acute leukaemia. J. Hosp. Infect., 5, 83-93. Gascoigne, E. W., Barton, G. J., Michaels, M., Meuldermans, W. & Heykants, J. (1981). The kinetics of ketoconazole in animals and man. Clin. Res. Rev., 1, 177-187. Hann, I. M., Prentice, H. G., Keaney, M., Corringham, R., Blacklock, H. A., Fox, J., Gascoigne, E. & van Cutsem, J. (1982). The pharmacokinetics of ketoconazole in severely immunocompromised patients. J. Antimicrob. Chemother., 10, 489-496. Lake-Bakaar, G., Cohen, P. & Strauss, E. W. (1988a). AIDS gastropathy: antibodies to gastric parietal cell. Gastroenterology, 94 (Part 2), A247. Lake-Bakaar, G., Tom, W., Gupta, N., Lake-Bakaar, D., Beidas, S., Elsakr, M. & Strauss, E. W.
(1988b). AIDS gastropathy: reversible ketoconazole malabsorption. Gastroenterology, 94 (Part 2), A247. Mannisto, P. T., Mantyla, R., Nykanen, S., Lamminsivu, U. & Ottoila, P. (1982). Impairing effect of food on ketoconazole absorption. Antimicrob. Agents Chemother., 21, 730-733. Stockley, R. J., Daneshmend, T. K., Bredow, M. T., Warnock, D. W., Richardson, M. D. & Slade, R. R. (1986). Ketoconazole pharmacokinetics during chronic dosing in adults with haematological malignancy. Eur. J. clin. Microbiol., 5, 513-517. Sutherland, C., Murphy, J. E. & Schleifer, N. H. (1983). The effects of two gastric acidifying agents on the pharmacokinetics of ketoconazole. Abstract. The American Society of Hospital Pharmacists. 18th Annual Midyear Clinical Meeting, Atlanta, Georgia, December 4-8. Van der Meer, J. W. M., Keuning, J. J., Scheijgrond, H. W., Heykants, J. & van Cutsem, J. (1980). Influence of gastric acidity on the bioavailability of ketoconazole. J. Antimicrob. Chemother., 6, 522524. Vu Van, H., Piens, M. A., Archimbaud, E., Monier, M. F., Goyotat, D., Mojon, M. & Fiere, D. (1983). Serum levels of ketoconazole in bone marrow transplanted patients. Nouvelle Revue Fran,aise d'Hematologie, 25, 241-244. Winstanley, P. A. & Orme, M. L'E. (1989). The effects of food on drug bioavailability. Br. J. clin. Pharmac., 28, 621-628.
