Clinical pharmacology of antibiotics and other drugs in cystic fibrosis.

The disposition of many drugs in cystic fibrosis is abnormal. In general, changes in pharmacokinetics include: increased volume of distribution, decreased plasma concentration, and enhanced renal and sometimes non-renal elimination of drugs. Pathophysiology of the disease important for drug disposition includes: (a) hypersecretion of gastric acid and duodenal secretions which are of small volume, viscous and low in bicarbonate; (b) increased intestinal permeability to some sugars and probe substances; (c) hypergammaglobulinaemia and sometimes hypoalbuminaemia; (d) significant elevation of free fatty palmitoleic acid level and decreased low-density and high-density serum lipoproteins; (e) an average increase by 30 to 45% in plasma volume in patients with cystic fibrosis who have moderately severe pulmonary disease, right ventricle hypertrophy and dilatation, which occurs in 15 to 35% of patients with a Shwachman score of 81 to 100; (f) abnormal bile acid metabolism and enterohepatic recirculation; and (g) enlarged kidneys and glomerulomegaly with increased glomerular filtration rate, tubular clearance and urine flow rate in some patients with cystic fibrosis. Delayed absorption from the gastrointestinal tract has been reported in patients with cystic fibrosis for cloxacillin, epicillin, clindamycin, ciprofloxacin and probably for cephalexin, para-aminobenzoic acid and chloramphenicol. A possible increased absorption was reported for cimetidine. Of 7 drugs studied only theophylline had significantly decreased plasma protein binding. An increased volume of distribution and increased renal clearance reported for several drugs is caused mainly by increases in plasma volume and urine flow rate in many of these patients. Possible increased elimination of some drugs in bile (which probably results from bile acid malabsorption) and in bronchial secretions (which are abundant in some cystic fibrosis patients with acute pulmonary infection) may explain enhanced non-renal elimination of these drugs. The metabolism of cimetidine in cystic fibrosis was reported not to be changed significantly compared to control subjects.