Duration of Grapefruit Juice Effect on Fexofenadine Interaction
1
CLINICALPHARMACOLOGY & THER,M)EUTICS P48 American Society for Clinical Pharmacology and Therapeutics FEBRUARY2003 PII-71 BRAIN AND SPINAL CORD DISTRIBUTION OF REFER- ENCE COMPOUNDS WITH VARYING DEGREES OF CNS PEN- ETRATION 1N A RAT MODEL OF CEREBRAL INFLAMMA- TION. S. Dantrev, PhD, D. Projean, BPharm, M. Roumi, PhD, J. Ducharme, PhD, AstraZeneca R&D Montreal, Universit6 de Mon- trdal, Montreal, Canada. In humans, conditions associated with cerebral inflammation, such as migraine or meningitis, can disrupt blood brain barrier integrity, which in turn may affect the entry of drugs into the CNS. To address this issue, we investigated the CNS distribution of reference com- pounds with varying degrees of CNS penetration in a rat model of cerebral inflammation induced by the intracerebroventricular (icy) administration of 2.4 p~g of lipopolysaccharides (LPS). Three and half hours later, LPS-treated or naive rats received 10 ixmol/kg iv of atenolol, quinidine or imipramine (n=5/group). At 30 rain, rats were sacrificed and a blood sample, brains (BR) and spinal cords (SC) were collected. Drug levels were measured by LC-MS. Atenolol, quinidine and imipramine were selected as representative compounds of low, medium and high CNS penetration, as evidenced by naive rat BR or SC to plasma ratios of d0.1, 1 and >40, respectively. In LPS-treated rats, atenolol remained peripherally restricted (CNS lev- els <0.05 nmol/g) while imipramine still penetrated the CNS very significantly (CNS levels >24 nmol/g). In contrast, CNS levels of quinidine were significantly increased (4-fold vs nfffve rats). This suggests that icy LPS administration does not affect the CNS pene- tration of passively transported drugs but may increase that of efflux system substrates like quinidine. Whether active transport systems like Pgp can be down regulated following icy LPS administration remains to be investigated. PII-72 POPULATION PHARMACOKINETICS OF OMEPRAZOLE IN HEALTHY ADULTS AND IN CHILDREN WITH CASTRO- ESOPHAGEAL REFLUX DISEASE. J. Marier, MSc, M. Dubuc, MSc, E. Drouin, MD, A. Fernando, MD, M. P. Ducharme, PharmD, J. Brazier, PhD, MDS Pharma Services/University of Montreal, St- Laurent (Montreal), Canada. The pharmacokinetic (PK) of omeprazole in children with gastro- esophageal reflux disease (GERD) remains scarce despite the vast amount of reports on its efficacy. The objective of this study was to assess the PK of omeprazole in healthy adults and in children with GERD. Omeprazole (Losec®, delayed-release capsule) was admin- istered orally to 18 healthy adults (Mean age: 36.8 +_5.6 years) and 12 children with GERD (Mean age: 6.1 -+4.4 years). Blood samples were collected over 5 h and plasma concentrations were assessed using liquid chromatography. Population PK parameters were calcu- lated using NONMEM®. A one-compartment model with zero-order rate constant of absorption and lag time was used. The population approach was well suited to the limited number of sample available and residual variability was low. Oral clearance (CL/F) and apparent volume of distribution (Vss/F) in healthy adults (0.62 +_0.27 L/h/kg and 0.76 -+0.26 L/kg, respectively) were not significantly different than those in children with GERD (0.51 +_0.34 L/h/kg and 0.66 +0.25 L/kg, respectively). Healthy adults displayed a statistically significant longer delay in drug absorption (Lag time: 0.62 -+0.15 h) as compared to that observed in children with GERD (0.12 +_0.30 h, p <0.05). These results confirm that no specific adjustments in omeprazole dosings (on a mg/kg basis) are necessary for the treat- ment of GERD in children. PII-73 DURATION OF GRAPEFRUIT JUICE EFFECT ON FEXOFE- NADINE INTERACTION. G.K. Dresser, MD~ R. B. Kim, MD, D. G. Bailey, PhD, Univ. of Western Ontario, London, ON & Vanderbilt Univ., Nashville, TN. Grapefruit juice (GFJ) reduces the oral bioavailability of fexofe- nadine (FEX), a non-metabolized substrate of certain OATP trans- porters. GFJ also interacts with CYP3A4 substrates even by juice given hours beforehand due to CYP3A4 inactivation. Prior GFJ ingestion was hypothesized to reduce FEX bioavailability. Twelve subjects received 300 ml GFJ or water (W) and FEX 120 mg in a randomized crossover study. GFJ was given at 0, 2, 4 or 10 hours prior to FEX. Results are shown (mean_+SE; *p<.05, **p<.01 ; GFJ vs W): GFJ-0 GFJ-2 GFJ-4 GFJ-10 W AUCo_ 8 948-+99** 1243-+156" 1918-+280 1691+233 1992-+265 C..... 236-+31" 281-+30" 428-+76 431-+76 457-+62 Duration of GFJ effect was highly variable among subjects. De- creased FEX AUC and C ..... were observed up to 10 hours in tour subjects. Previous GFJ reduces FEX bioavailability possibly by irre- versible inactivation of intestinal OATP activity. PII-74 VOLUME OF GRAPEFRUIT JUICE AND BIOAVAILABILITY OF FEXOFENADINE. D. G. Bailey, PhD, G. K. Dresser, MD, R. B. Kim, MD, Univ. of Western Ontario, London, ON & Vanderbilt Univ., Nashville, TN. Grapefruit juice (GFJ) decreases the bioavailability of fexofena- dine (FEX), a non-metabolized substrate of certain OATP transport- ers. Although GFJ potently inhibits OATP in vitro, volume may also contribute by decreasing FEX concentration and duration at tile intestinal OATP receptor. Low volume was hypothesized to produce greater bioavailability of FEX than high volume. Twelve subjects received flEX 120 mg with 300 ml (given acutely) or 1200 ml (over 3 h) GFJ or W in a randomized crossover study. FEX results are shown (mean_+SE; *p<.01,300 v 1200; !p<.001,GFJ v W): GFJ-300 GFJ-1200 W-300 W-1200 AUCo 8 980-+68"! 494-+28! 1684+236 1378-+155 C..... 233-+25"! 109-+8! 436-+74 326+37 Decreased volume of GFJ enhances FEX bioavailability. A normal amount of GFJ produces a clinically relevant interaction with FEX. Direct inhibition of OATP and indirect effects by GFJ in the gut are likely involved.
Transcript of Duration of Grapefruit Juice Effect on Fexofenadine Interaction
CLINICAL PHARMACOLOGY & THER,M)EUTICS P 4 8 American Society for Clinical Pharmacology and Therapeutics FEBRUARY2003
PII-71 BRAIN AND SPINAL CORD DISTRIBUTION OF REFER-
ENCE COMPOUNDS WITH VARYING DEGREES OF CNS PEN- ETRATION 1N A RAT MODEL OF CEREBRAL INFLAMMA- TION. S. Dantrev, PhD, D. Projean, BPharm, M. Roumi, PhD, J. Ducharme, PhD, AstraZeneca R&D Montreal, Universit6 de Mon- trdal, Montreal, Canada.
In humans, conditions associated with cerebral inflammation, such as migraine or meningitis, can disrupt blood brain barrier integrity, which in turn may affect the entry of drugs into the CNS. To address this issue, we investigated the CNS distribution of reference com- pounds with varying degrees of CNS penetration in a rat model of cerebral inflammation induced by the intracerebroventricular (icy) administration of 2.4 p~g of lipopolysaccharides (LPS). Three and half hours later, LPS-treated or naive rats received 10 ixmol/kg iv of atenolol, quinidine or imipramine (n=5/group). At 30 rain, rats were sacrificed and a blood sample, brains (BR) and spinal cords (SC) were collected. Drug levels were measured by LC-MS. Atenolol, quinidine and imipramine were selected as representative compounds of low, medium and high CNS penetration, as evidenced by naive rat BR or SC to plasma ratios of d0.1, 1 and >40, respectively. In LPS-treated rats, atenolol remained peripherally restricted (CNS lev- els <0.05 nmol/g) while imipramine still penetrated the CNS very significantly (CNS levels >24 nmol/g). In contrast, CNS levels of quinidine were significantly increased (4-fold vs nfffve rats). This suggests that icy LPS administration does not affect the CNS pene- tration of passively transported drugs but may increase that of efflux system substrates like quinidine. Whether active transport systems like Pgp can be down regulated following icy LPS administration remains to be investigated.
PII-72 POPULATION PHARMACOKINETICS OF OMEPRAZOLE IN
HEALTHY ADULTS AND IN CHILDREN WITH CASTRO- ESOPHAGEAL REFLUX DISEASE. J. Marier, MSc, M. Dubuc, MSc, E. Drouin, MD, A. Fernando, MD, M. P. Ducharme, PharmD, J. Brazier, PhD, MDS Pharma Services/University of Montreal, St- Laurent (Montreal), Canada.
The pharmacokinetic (PK) of omeprazole in children with gastro- esophageal reflux disease (GERD) remains scarce despite the vast amount of reports on its efficacy. The objective of this study was to assess the PK of omeprazole in healthy adults and in children with GERD. Omeprazole (Losec®, delayed-release capsule) was admin- istered orally to 18 healthy adults (Mean age: 36.8 +_5.6 years) and 12 children with GERD (Mean age: 6.1 -+4.4 years). Blood samples were collected over 5 h and plasma concentrations were assessed using liquid chromatography. Population PK parameters were calcu- lated using NONMEM®. A one-compartment model with zero-order rate constant of absorption and lag time was used. The population approach was well suited to the limited number of sample available and residual variability was low. Oral clearance (CL/F) and apparent volume of distribution (Vss/F) in healthy adults (0.62 +_0.27 L/h/kg and 0.76 -+0.26 L/kg, respectively) were not significantly different than those in children with GERD (0.51 +_0.34 L/h/kg and 0.66 +0.25 L/kg, respectively). Healthy adults displayed a statistically significant longer delay in drug absorption (Lag time: 0.62 -+0.15 h) as compared to that observed in children with GERD (0.12 +_0.30 h, p <0.05). These results confirm that no specific adjustments in omeprazole dosings (on a mg/kg basis) are necessary for the treat- ment of GERD in children.
PII-73 DURATION OF GRAPEFRUIT JUICE EFFECT ON FEXOFE-
NADINE INTERACTION. G.K. Dresser, MD~ R. B. Kim, MD, D. G. Bailey, PhD, Univ. of Western Ontario, London, ON & Vanderbilt Univ., Nashville, TN.
Grapefruit juice (GFJ) reduces the oral bioavailability of fexofe- nadine (FEX), a non-metabolized substrate of certain OATP trans- porters. GFJ also interacts with CYP3A4 substrates even by juice given hours beforehand due to CYP3A4 inactivation. Prior GFJ ingestion was hypothesized to reduce FEX bioavailability. Twelve subjects received 300 ml GFJ or water (W) and FEX 120 mg in a randomized crossover study. GFJ was given at 0, 2, 4 or 10 hours prior to FEX. Results are shown (mean_+SE; *p<.05, **p<.01 ; GFJ vs W):
GFJ-0 GFJ-2 GFJ-4 GFJ-10 W
AUCo_ 8 948-+99** 1243-+156" 1918-+280 1691+233 1992-+265 C ..... 236-+31" 281-+30" 4 2 8 - + 7 6 4 3 1 - + 7 6 457-+62
Duration of GFJ effect was highly variable among subjects. De- creased FEX AUC and C ..... were observed up to 10 hours in tour subjects. Previous GFJ reduces FEX bioavailability possibly by irre- versible inactivation of intestinal OATP activity.
PII-74 VOLUME OF GRAPEFRUIT JUICE AND BIOAVAILABILITY
OF FEXOFENADINE. D. G. Bailey, PhD, G. K. Dresser, MD, R. B. Kim, MD, Univ. of Western Ontario, London, ON & Vanderbilt Univ., Nashville, TN.
Grapefruit juice (GFJ) decreases the bioavailability of fexofena- dine (FEX), a non-metabolized substrate of certain OATP transport- ers. Although GFJ potently inhibits OATP in vitro, volume may also contribute by decreasing FEX concentration and duration at tile intestinal OATP receptor. Low volume was hypothesized to produce greater bioavailability of FEX than high volume. Twelve subjects received flEX 120 mg with 300 ml (given acutely) or 1200 ml (over 3 h) GFJ or W in a randomized crossover study. FEX results are shown (mean_+SE; *p<.01 ,300 v 1200; !p<.001,GFJ v W):
GFJ-300 GFJ-1200 W-300 W-1200
AUCo 8 9 8 0 - + 6 8 " ! 4 9 4 - + 2 8 ! 1684+236 1378-+155 C ..... 233-+25"! 109-+8! 436-+74 326+37
Decreased volume of GFJ enhances FEX bioavailability. A normal amount of GFJ produces a clinically relevant interaction with FEX. Direct inhibition of OATP and indirect effects by GFJ in the gut are likely involved.
