Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time.
During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80-120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 microCi 111 InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.
Department of Clinical Pharmacology, Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709.
K M
KM
Koch
A F
AF
Parr
J J
JJ
Tomlinson
E P
EP
Sandefer
G A
GA
Digenis
K H
KH
Donn
J R
JR
Powell
D000328:Adult; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D011756:Diphosphates / Q000494:pharmacology*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007205:Indium Radioisotopes; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D011899:Ranitidine / Q000493:pharmacokinetics*; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D013607:Tablets
D011756:Diphosphates; D007205:Indium Radioisotopes; D012996:Solutions; D013607:Tablets; D011899:Ranitidine; C003319:sodium pyrophosphate