Intragastric pH and pharmacokinetics of intravenous ranitidine during sinusoidal and constant-rate infusions.
Six patients with healed duodenal ulcer completed two treatment periods with continuous i.v. infusion ranitidine. A 25-mg i.v. bolus was followed by a constant infusion at 6.25 mg/h or a sinusoidal infusion with infusion rates ranging from 3.125 to 9.375 mg/h. The sinusoidal infusion rate was designed to match the previously observed circadian changes in basal acid secretion. The peak infusion rate occurred at 19:30 h. A pharmacokinetic method was designed to predict the resultant plasma concentrations of ranitidine. Intragastric pH and plasma ranitidine concentration data were fit to a cosine function to evaluate circadian and ultradian rhythms. Plasma concentrations during the sinusoidal infusion exhibited a circadian rhythm according to model predictions. Cosinor analyses of the mean ranitidine plasma concentration data showed a mesor concentration of 237 ng/mL and amplitude of 76 ng/mL (coefficient of determination [CD] = 0.98). The acrophase in plasma concentration occurred at 2223 h, a delay of approximately 2.9 hours from the peak in the infusion rate. The constant-rate infusion resulted in a mean plasma concentration of 222 +/- 32 ng/mL. The 24-h mean intragastric pH values for the sinusoidal and constant regimens were 5.4 and 5.1, respectively (p = 0.170). The intragastric pH during the constant-rate infusion exhibited a significant circadian rhythm (CD = 0.52). The minimum pH (bathy-phase) occurred at 2031 h. No circadian rhythm was present during the sinusoidal-rate infusion (CD = 0.08). At the approximate time of the peak basal acid secretion, between 21:00 hours and midnight, the mean pH for the sinusoidal infusion was 5.77 versus 4.5 for the constant-rate infusion (p = 0.112). Sinusoidal infusions or alternate methods of increased doses at the times of peak acid output may improve around-the-clock control of intragastric pH.
Sanders
S W
SW
Drug Research Center, University of Utah Medical Center, Salt Lake City 84132.
Bishop
A L
AL
Moore
J G
JG
D000328:Adult; D000368:Aged; D002940:Circadian Rhythm / Q000502:physiology*; D004381:Duodenal Ulcer / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011899:Ranitidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D011899:Ranitidine