Lack of effect of P-glycoprotein inhibition on renal clearance of dicloxacillin in patients with cystic fibrosis.
OBJECTIVE
To determine whether upregulation of P-glycoprotein is responsible for the enhanced renal clearance of dicloxacillin in patients with cystic fibrosis.


METHODS
Single-center, prospective, open-label, randomized, three-part crossover pharmacokinetic study.


METHODS
General clinical research center.


METHODS
Eleven patients with cystic fibrosis and 11 age-matched healthy volunteers.


METHODS
All subjects received a single oral dose of dicloxacillin 500 mg alone, dicloxacillin 500 mg plus probenecid (an organic anion transport inhibitor) 1 g, and dicloxacillin 500 mg plus cyclosporine (a P-glycoprotein inhibitor) 5 mg/kg; each treatment was separated by a washout period of 48 hours. A bolus dose of iothalamate meglumine 456 mg was administered on each study day as a marker of glomerular filtration.


RESULTS
Blood and urine samples were taken serially up to 6 hours after each dose. Pharmacokinetics of dicloxacillin and iothalamate were determined by using compartmental and noncompartmental methods. Quantitative polymerase chain reaction was performed on peripheral blood mononuclear cells to measure expression of multidrug resistance 1 (MDR1) messenger RNA (mRNA). Genotyping for ABCB1 was performed to determine the presence of single nucleotide polymorphisms (exons 21 and 26). In both healthy subjects and patients with cystic fibrosis, compared with dicloxacillin alone, coadministration with probenecid produced a significantly lower renal clearance of dicloxacillin, whereas coadministration with cyclosporine resulted in no significant change; renal clearance was not significantly different between the two study groups. No correlation was found between MDR1 mRNA expression and renal clearance of dicloxacillin. The renal excretion of dicloxacillin was significantly greater in subjects with the ABCB1 exon 26 TT polymorphism when compared with subjects with the CT genotype.


CONCLUSIONS
We found no significant difference in the pharmacokinetics of dicloxacillin between patients with cystic fibrosis and healthy volunteers. Renal clearance of dicloxacillin was significantly reduced in the presence of probenecid but not with cyclosporine, suggesting that the rate-limiting step in tubular secretion of dicloxacillin is uptake mediated by the organic anion transporter, and not P-glycoprotein inhibition.
Beringer
Paul M
PM
Department of Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA. beringer@usc.edu
Kriengkauykiat
Jane
J
Zhang
Xiyun
X
Hidayat
Levita
L
Liu
Shanshan
S
Louie
Stan
S
Synold
Tim
T
Burckart
Gilbert J
GJ
Rao
Purush A
PA
Shapiro
Bertrand
B
Gill
Mark
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003287:Contrast Media; D016572:Cyclosporine / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000503:physiopathology*; D004009:Dicloxacillin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007482:Iothalamate Meglumine; D007668:Kidney / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics; D011110:Polymorphism, Genetic; D011339:Probenecid / Q000494:pharmacology; D011446:Prospective Studies
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D003287:Contrast Media; D027361:Organic Anion Transporters; D016572:Cyclosporine; D004009:Dicloxacillin; D011339:Probenecid; D007482:Iothalamate Meglumine