Abstract
There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition.
Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs studied did not differ in patients with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy individuals vanished when corrected for lean body mass.
Despite hepatic dysfunction, patients with CF have enhanced clearance of many, but not all, drugs. Phase I mixed-function oxidases are selectively affected: cytochrome P450 (CYP) 1A2 and CYP2C8 have enhanced activity, while other CYP isoforms such as CYP2C9 and CYP3A4 are unaffected. Increased phase II activities are also demonstrated: glucuronyl transferase, acetyl transferase (NAT1) and sulfotransferase. The increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver.
The renal clearance (CLr) of many drugs in patients with CF is enhanced although there has been no pathological abnormality identified which could explain this finding: glomerular filtration rate and tubular secretion appear normal in patients with CF. The precise mechanisms for enhanced drug clearance in patients with CF remain to be elucidated.
The optimisation of antibiotic therapy in patients with CF includes increasing the dose of β-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides. The appropriate dosage of quinolones has not been definitively established.
Similar content being viewed by others
References
Cox KL, Isenberg JN, Ament ME. Gastric acid hypersecretion in cystic fibrosis. J Pediatr Gastroenterol Nutr 1982; 1: 559–65.
Fondacaro JD, Heubi JE, Kellogg FW. Intestinal bile acid malabsorption in cystic fibrosis: a primary mucosal cell defect. Pediatr Res 1982; 16: 494–8.
Spino M, Chai RP, Isles AF, et al. Cloxacillin absorption and disposition in cystic fibrosis. J Pediatr 1984; 105: 829–35.
Goldfarb J, Wormser GP, Inchiosa MA, et al. Single-dose pharmacokinetics of oral ciprofloxacin in patients with cystic fibrosis. J Clin Pharmacol 1986; 26: 222–6.
Bender SW, Dalholff A, Shah PM, et al. Ciprofloxacin pharmacokinetics in patients with cystic fibrosis. Infection 1986; 14: 17–21.
Lebel M, Bergeron MG, Vallée F, et al. Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis patients. Antimicrob Agents Chemother 1986; 30: 260–6.
Reed MD, Stern RC, Myers CM, et al. Lack of unique ciprofloxacin pharmacokinetic characteristics in patients with cystic fibrosis. J Clin Pharmacol 1988; 28: 691–9.
Christensson BA, Nilsson-Ehle I, Ljungberg B, et al. Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients. Antimicrob Agents Chemother 1992; 36: 2512–7.
Spino M, Bentur Y, Martin S, et al. Enoxacin disposition in patients with cystic fibrosis (CF) and healthy control subjects [abstract]. Eur J Clin Pharmacol 1989; 36 Suppl.: A84.
Mimeault J, Vallée F, Seelmann R, et al. Altered disposition of fleroxacin in patients with cystic fibrosis. Clin Pharmacol Ther 1990; 47: 618–28.
Isles A, Spino M, Tabachnik E, et al. Theophylline disposition in cystic fibrosis. Am Rev Respir Dis 1983; 127: 417–21.
Ziemniak JA, Assael BM, Padoan R, et al. The bioavailability and pharmacokinetics of cimetidine and its metabolites in juvenile cystic fibrosis patients: age related differences as compared to adults. Eur J Clin Pharmacol 1984; 26: 183–9.
Grahnén A, Von Bahr C, Lindström B, et al. Bioavailability and pharmacokinetics of cimetidine. Eur J Clin Pharmacol 1979; 16: 335–40.
Cooney GF, Fiel SB, Shaw LM, et al. Bioavailability of oral cyclosporine-Ain heart-lung transplant candidates with cystic fibrosis [abstract]. Clin Pharmacol Ther 1989; 45: 140.
Tan KKC, Trull AK, Hue KL, et al. Pharmacokinetics of cyclosporine in heart and lung transplant candidates and recipients with fibrosis and Eisenmenger’s syndrome. Clin Pharmacol Ther 1993; 53: 544–54.
Tsang VT, Johnston A, Heritier F, et al. Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis. Eur J Clin Pharmacol 1994; 46: 261–5.
Tan KKC, Trail AK, Uttridge JA. Relative bioavailability of cyclosporin from conventional and microemulsion formulations in heart-lung transplant candidates with cystic fibrosis. Eur J Clin Pharmacol 1995; 48: 285–9.
Reynaud-Gaubert M, Viard L, Girault D, et al. Improved absorption and bioavailability of cyclosporine A from a microemulsion formulation in lung transplant recipients affected with cystic fibrosis. Transplant Proc 1997; 29: 2450–3.
Friman S, Bäckman L. A new microemulsion formulation of cyclosporin: pharmacokinetic and clinical features. Clin Pharmacokinet 1996; 30: 181–93.
Davis RL, Koup JR, Williams-Warren J, et al. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Antimicrob Agents Chemother 1987; 31: 915–9.
Strober W, Peter G, Schwartz RH. Albumin metabolism in cystic fibrosis. Pediatrics 1969; 43: 416–26.
Schwartz RH. Serum immunoglobulin levels in cystic fibrosis. Am J Dis Child 1960; 111: 408–11.
Jusko WJ, Mosovich LL, Gerbracht LM, et al. Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatrics 1975; 56: 1038–44.
Arvidsson A, Alván G, Strandvik B. Difference in renal handling of cefsulodin between patients with cystic fibrosis and normal subjects. Acta Paediatr Scand 1983; 72: 293–4.
Leeder JS, Spino M, Isles AF, et al. Ceftazidime disposition in acute and stable cystic fibrosis. Clin Pharmacol Ther 1984; 36: 355–62.
Levy J, Smith AL, Koup JR, et al. Disposition of tobramycin in patients with cystic fibrosis: a prospective controlled study. J Pediatr 1984; 105: 117–24.
Knoppert DC, Spino M, Beck R, et al. Cystic fibrosis: enhanced theophylline metabolism may be linked to the disease. Clin Pharmacol Ther 1988; 44: 254–64.
Hutabarat RM, Unadkat JD, Sahajwalla C, et al. Disposition of drugs in cystic fibrosis: I. Sulfamethoxazole and trimethoprim. Clin Pharmacol Ther 1991; 49: 402–9.
Wang JP, Unadkat JD, McNamara S, et al. Disposition of drugs in cystic fibrosis: VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis. Clin Pharmacol Ther 1994; 55: 528–34.
O’sullivan T, Wang JP, Unadkat JD, et al. Disposition of drags in cystic fibrosis: V In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis. Clin Pharmacol Ther 1993, 54: 323–8.
Rosenthal A, Button LN, Khaw KT. Blood volume changes in patients with cystic fibrosis. Pediatrics 1977; 59: 588–94.
Finkelstein E, Hall K. Aminoglycoside clearance in patients with cystic fibrosis. J Pediatr 1979; 94: 163–4.
Kearns GL, Hilman BC, Wilson JT. Dosing implications of altered gentamicin disposition in patients with cystic fibrosis. J Pediatr 1982; 100: 312–8.
Yaffe SJ, Gerbracht LM, Mosovich LL, et al. Pharmacokinetics of methicillin in patients with cystic fibrosis. J Infect Dis 1977; 135: 828–31.
De Groot R, Hack BD, Weber A, et al. Pharmacokinetics of ticarcillin in patients with cystic fibrosis: a controlled prospective study. Clin Pharmacol Ther 1990; 47: 73–8.
Prandota J. Drug disposition in cystic fibrosis: progress in understanding pathophysiology and pharmacokinetics. Pediatr Infect Dis J 1987; 6: 1111–26.
Morgan DJ, Bray KM. Lean body mass as a predictor of drag dosage: implications for drag therapy. Clin Pharmacokinet 1994; 26: 292–307.
Kearns GL. Hepatic drug metabolism in cystic fibrosis: recent developments and future directions. Ann Pharmacother 1993; 27: 74–9.
Isenberg JN. Cystic fibrosis: its influence on the liver, biliary tree, and bile salt metabolism. Semin Liver Dis 1982; 2: 302–13.
Vergesslich KA, Götz M, Mostbeck G, et al. Portal venous blood flow in cystic fibrosis: assessment by duplex Doppler sonography. Pediatr Radiol 1989; 19: 371–4.
O’sullivan T, Bauer LA, Horn JR, et al. Disposition of drugs in cystic fibrosis: II. Hepatic blood flow. Clin Pharmacol Ther 1991; 50: 450–5.
Kearns GL, Mallory GB, Crom WR, et al. Enhanced hepatic drug clearance in patients with cystic fibrosis. J Pediatr 1990; 117: 972–9.
Kearns GL, Crom WR, Karlson KH, et al. Hepatic drug clearance in patients with mild cystic fibrosis. Clin Pharmacol Ther 1996; 59: 529–40.
Tan KKC, Hue KL, Strickland SE, et al. Altered pharmacokinetics of cyclosporin in heart-lung transplant recipients with cystic fibrosis. Ther Drug Monit 1990; 12: 520–4.
Bentur Y, Spino M, Gold R, et al. Enhanced ciprofloxacin clearance in cystic fibrosis (CF) patients [abstract]. Clin Pharmacol Ther 1990; 47: 185.
Spino M, Henderson K, MacLeod SM, et al. Cisapride [abstract]. Clin Invest Med 1988; 11: 17.
Alván G, Beermann B, Hjelte L, et al. Increased nonrenal clearance and increased diuretic efficiency of furosemide in cystic fibrosis. Clin Pharmacol Ther 1988; 44: 436–41.
Konstan MW, Hoppel CL, Chai B, et al. Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects. J Pediatr 1991; 118: 956–64.
Reed MD, Stern RC, Bertino JS, et al. Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with cystic fibrosis. J Pediatr 1984; 104: 303–7.
Hutabarat RM, Unadkat JD, Kushmerick P, et al. Disposition of drugs in cystic fibrosis: III. Acetaminophen. Clin Pharmacol Ther 1991; 50: 695–701.
Dranitsaris G, Spino M, Tesoro A, et al. Theophylline (THEO) biotransformation in normal and diseased human livers [abstract]. Clin Pharmacol Ther 1992; 51: 162.
Parker AC, Pritchard P, Preston T, et al. Enhanced drug metabolism in young children with cystic fibrosis. Arch Dis Child 1997; 77: 239–41.
Hamelin BA, Xu K, Vallé F, et al. Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity. Clin Pharmacol Ther 1994; 56: 521–9.
Bosso JA, Liu Q, Evans WE, et al. CYP2D6, N-acetylation, and xanthine oxidase activity in cystic fibrosis. Pharmacotherapy 1996; 16: 749–53.
Albert KS, Gernaat CM. Pharmacokinetics of ibuprofen. Am J Med 1984; 77 Suppl. 1A: 40–6.
Hutabarat RM, Smith AL, Unadkat JD. Disposition of drugs in cystic fibrosis. VII. Acetylation of sulfamethoxazole in blood cells: in vitro-in vivo correlation and characterization of its kinetics of acetylation in lymphocytes. Clin Pharmacol Ther 1994; 55: 427–33.
Weinberger MM. Drug clearance in patients with cystic fibrosis [letter]. Clin Pharmacol Ther 1992; 52: 106.
Berg U, Kusoffsky E, Strandvik B. Renal function in cystic fibrosis with special reference to the renal sodium handling. Acta Paediatr Scand 1982; 71: 833–8.
Michalsen H, Monn E, Bergan T, et al. Renal biopsies in cystic fibrosis. Pathol Res Pract 1984; 178: 261–7.
Spino M, Chai RP, Isles AF, et al. Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis. J Pediatr 1985; 107: 64–70.
Prandota J. Clinical pharmacology of antibiotics and other drugs in cystic fibrosis. Drugs 1988; 35: 542–78.
Michalsen H, Bergan T. Pharmacokinetics of netilmicin in children with and without cystic fibrosis. Antimicrob Agents Chemother 1981; 19: 1029–31.
Hedman A, Alván G, Strandvik B, et al. Increased renal clearance of cefsulodin due to higher glomerular filtration rate in cystic fibrosis. Clin Pharmacokinet 1990; 18: 168–75.
Hedman A, Adan-Abdi Y, Alvá G, et al. Influence of the glomerular filtration rate on renal clearance of ceftazisime in cystic fibrosis. Clin Pharmacokinet 1988; 15: 57–65.
Sörgel F, Stephan U, Wiesemann HG, et al. High dose treatment with antibiotics in cystic fibrosis: a reappraisal with special reference to the pharmacokinetics of betalactams and new fluoroquinolones in adult CF-patients. Infection 1987; 15: 385–96.
Pechere JC, Dugal R. Clinical pharmacokinetics of aminoglycoside antibiotics. Clin Pharmacokinet 1979; 4: 170–99.
Wang JP, Unadkat JD, Al-Habet SMH, et al. Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin. Clin Pharmacol Ther 1993; 54: 293–302.
Vance-Bryan K, Guay DRP, Rotschafer JC. Clinical pharmacokinetics of ciprofloxacin. Clin Pharmacokinet 1990; 19: 434–61.
Spino M. Pharmacokinetics of drugs in cystic fibrosis. Clin Rev Allergy 1990; 9: 169–210.
Strandvik B, Berg U, Kallner A, et al. Effect on renal function of essential fatty acid supplementation in cystic fibrosis. J Pediatr 1989; 115: 242–50.
Lindsay CA, Bosso JA. Optimisation of antibiotic therapy in cystic fibrosis patients. Clin Pharmacokinet 1993; 24: 496–506.
Bosso JA, Townsend PL, Herbst JJ, et al. Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients. Antimicrob Agents Chemother 1985; 28: 829–31.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rey, E., Tréluyer, JM. & Pons, G. Drug Disposition in Cystic Fibrosis. Clin Pharmacokinet 35, 313–329 (1998). https://doi.org/10.2165/00003088-199835040-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199835040-00004