Clinical Pharmacology of Antibiotics and Other Drugs in Cystic Fibrosis

Abstract

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.

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

“…Aminoglycosides diffuse poorly across lipid membranes and into bronchial secretions and their distribution is mainly restricted to the extracellular fluid. Although tobramycin has the highest penetration into bronchial secretions of aminoglycosides studied [62,63], relatively high dosages are needed when the drug is given parenterally. Therefore, it is generally recommended to administer aminoglycosides by inhalation for maintenance therapy.…”

Assessment of arylamine N‐acetyltransferase (NAT1) activity in mononuclear leukocytes of cystic fibrosis patients.

“…Changes in either of these two pathways could change the equilibrium in favour of acetylSMX formation and appear as an apparent enhanced metabolism without necessitating changes in the activity of N-acetyltransferase enzymes. Increased urinary excretion of compounds actively secreted by the organic acid transporter proteins has been described in cystic fibrosis [1,6] and acetylSMX is known to be actively secreted by this pathway [21]. This hypothesis could be tested by the determination of the clearance of acetylSMX in cystic fibrosis patients.…”

“…The rate of elimination of many drugs is increased in cystic fibrosis patients, necessitating changing the normal dosing rate to achieve a therapeutic benefit [1]. Pharmacokinetic studies have shown increased total clearance, changes in the apparent volume of distribution, increased renal clearance and evidence of enhanced metabolism [1][2][3][4][5][6].…”

“…Pharmacokinetic studies have shown increased total clearance, changes in the apparent volume of distribution, increased renal clearance and evidence of enhanced metabolism [1][2][3][4][5][6]. The basis for the apparent enhanced metabolism of drugs has not been determined [7].…”

Plasma concentrations and effects of salbutamol administered orally to patients with cystic fibrosis.

“…Patients with cystic fibrosis (CF) present pathophysiological and biochemical abnormalities that may lead to altered pharmacokinetics [1,2]. It has been reported that the clearance and volume of distribution of a number of drugs, including dicloxacillin, epicillin, cephaxillin, methicillin, gentamicin, tobramycin, amikacin, theophylline, furosemide, cimetidine and paracetamol [3][4][5][6][7][8][9][10][11][12][13] are increased in CF patients.…”