1185 Pharmacokinetics and Bioavailability of a Sustainedrelease Theophylline Preparation (Theodur) in Cystic Fibrosis (Cf)

Abstract

Med.Ctr., Rockefeller Univ. NY, Lava1 Univ. Quebec Extensive metabolic and enzymatic studies i n a patient with hereditary hepatorenal tyrosinemia demonstrated f o r the f i r s t time a deficiency of red c e l l and hepatic glutathione (GSH). Markedly decreased hepatic fumarylacetoacetate hydrolase a c t i v i t y was measured i n t h i s patient (1-16% of normal). The a c t i v i t y of enzymes not involved i n tyrosine metabolism were a l s o measured i n l i v e r tissue. Assay of mixed function oxidase a c t i v i t y demonstrated low levels of arylhydrocarbon hydroxylase and 7-ethoxycoumarindeethylase. This depression of mixed function oxidase activity'may r e s u l t i n a decreased detoxification capacity of t h e l i v e r . Delta-amino levulinic acid dehydratase (ALAD) a c t i v i t y was undetectable. Succinyl acetone (4,6 dioxoheptanoic a c i d ) , an abnormal metabolic product secondary t o the fumarylacetoacetate hydrolase deficiency, was measurable i n serum and urine. Succinyl acetone was demonstrated t o i n h i b i t ALAD _In_ v i t r o , as did the urine, plasma and red c e l l l y s a t e s of t h e -p a t i e n t . The decreased GSH observed i n t h i s condition may play a r o l e i n the hepatic pathology and increased malignant p o t e n t i a l i n t h i s disorder. Therefore, the decrease i n GSH demonstrated i n our patient suggests the p o s s i b i l i t y of a new mode of therapy. W e studied t h e e f f e c t of 1,25(OH)2D3 on phosphate (Pi) homeos t a s i s i n the H mouse, a homologue of X-linked hypophosphatemia i n man. 1 ,25($2D3 (83 pg/g.day, infused subcut. x 10 days) produced s i g n i f i c a n t hypercalcemia in normal mice (1 1 .34+0.07 vs . W e conclude t h a t 1,25(OH)2D3 does not correct the renal BBM transport defect in rn mice, a t t h e supraphysiologic dose t h a t improves Pi homeostas i s . On t h e other hand, 1,25(OH)2~3 enhances ( p < 0 . 0 2 ) . i n t e s t inal absorption of Pi i n t h e m m o u s e , thus explaining i t s e f f e c t on Pi homeostasis i n t h e mutant phenotype of mouse and man. PERSISTANCE OF THE DEFECT IN RENAL BRUSH-BORDER MEM- 1184 PHARMACOKINETICS AND BIOAVAILABILITY OF A SUSTAINED-RELEASE THEOPHYLLINE PREPARATION (THEODUR) IN CYSTIC'Ig5 FIBROSIS (CF). Scott 8. Valet, Robert H. Schwartr, and John G. Brooks, University of R o c h e s t e r m o T of Medicine and m i r t r -t . Ped. Rochester, New York. Theophyll ine (theoph,) improves lung function in some CF pat i e n t s . Pharmacoki netics and bi oavai l abi l i t y of oral theoph, a r e not defined f o r these patients. W e studied the elimination of theoph. a f t e r IV Aminophylline,andabsorption of sustainedrelease oral theoph.(Theodur) in 10 CF patients (age 10-48 y r s ) . Each received a bolus of aminophyll i n e (4 mg/kg anhydrous theoph. ) and 10 plasma theophs.levels were measured over 8 hrs.El imination h a l f -l i f e (Tlg), t o t a l body clearance (Cl), volume of distribution (Vd) and area under the concentration curve (AUCiv) were determined.Two days l a t e r each pa...

Clinical Pharmacokinetics in Infants and Children A Reappraisal

“…This enhanced clearance was attributed to an increased formation of I-methylxan- These results appear to support enhanced hepatic microsomal enzyme activity for the pathways responsible for theophylline biotransformation in patients with cystic fibrosis. Data from 2 previous investigations revealed linear inverse correlations between theophylline total body clearance and NIH scores (Larsen et al 1980;Valet et al 1983). These observations further suggest that theophylline clearance in cystic fibrosis patients increases as disease severity worsens, a finding similar to that reported for gentamicin clearance in cystic fibrosis patients (MacDonald et al 1983).…”

“…Before firm conclusions regarding these apparent differences can be reached, the disposition of cimetidine and its metabolites must be evaluated in adults with this disease. The pharmacokinetics of theophylline have been previously evaluated in cystic fibrosis patients larsen et al 1980;Valet et al 1983). In the only controlled investigation, Isles et al (1983) found that the total body clearance oftheophylline in cystic fibrosis patients (0.075 ± 0.028 L/h/kg) was approximately twice as high as that observed in healthy control subjects (0.035 ± 0.003 L/h/kg).…”

Pharmacokinetics and Diffusion into Sputum of Oseltamivir and Oseltamivir Carboxylate in Adults with Cystic Fibrosis

“…First, oseltamivir is a prodrug that is converted to the active compound, oseltamivir carboxylate (OC), via first-pass metabolism by hepatic esterases (6). The production of carboxylate could therefore be modified in CF patients since CF can change drug bioavailability (10,26). Second, the aqueous distribution volume and renal clearance of drugs are often increased in CF patients (24).…”