DRUG DISPOSITION IN CYSTIC-FIBROSIS

There are many pathological changes in patients with cystic fibrosis ( CF) which can lead to alterations in drug disposition. Although, in pa tients with CF, the extent of drug absorption varies widely and the ra te of absorption is slower, bioavailability is not altered. Plasma pro tein binding for the majority of drugs studied did not differ in patie nts with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy indivi duals vanished when corrected for lean body mass. Despite hepatic dysf unction, patients with CF have enhanced clearance of many, but not all , drugs. Phase I mixed-function oxidases are selectively affected: cyt ochrome 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 t ransferase (NAT1) and sulfotransferase. The increased hepatic clearanc e of drugs in the presence of CF may be the consequence of disease-spe cific 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 identifi ed which could explain this finding: glomerular filtration rate and tu bular secretion appear normal in patients with CE The precise mechanis ms for enhanced drug clearance in patients with CF remain to be elucid ated. The optimisation of antibiotic therapy in patients with CF inclu des increasing the dose of beta-lactams by 20 to 30% and monitoring pl asma concentrations of aminoglycosides. The appropriate dosage of quin olones has not been definitively established.