The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil.
The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead-in period done under fasting conditions, followed by randomization to a four-way crossover of pentagastrin (6 micrograms/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration-time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p less than 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p less than 0.0001 for both). In the food study (n = 16 subjects), there were two lead-in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four-way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p less than 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.
Hughes
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GS
Upjohn Research Clinics, Upjohn Company, Kalamazoo, MI 49007.
Heald
D L
DL
Barker
K B
KB
Patel
R K
RK
Spillers
C R
CR
Watts
K C
KC
Batts
D H
DH
Euler
A R
AR
D000284:Administration, Oral; D000328:Adult; D000536:Aluminum Hydroxide / Q000494:pharmacology; D001639:Bicarbonates / Q000494:pharmacology; D015296:Ceftizoxime / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004041:Dietary Fats / Q000008:administration & dosage; D004044:Dietary Proteins / Q000008:administration & dosage; D004952:Esters; D005215:Fasting; D005502:Food; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D015394:Molecular Structure; D010418:Pentagastrin / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D011899:Ranitidine / Q000494:pharmacology; D012044:Regression Analysis; D012964:Sodium / Q000494:pharmacology; D017693:Sodium Bicarbonate; D013270:Stomach / Q000187:drug effects; D000097623:Cefpodoxime
D000536:Aluminum Hydroxide; D001639:Bicarbonates; D015296:Ceftizoxime; D004041:Dietary Fats; D004044:Dietary Proteins; D004952:Esters; D010418:Pentagastrin; D011355:Prodrugs; D011899:Ranitidine; D012964:Sodium; D017693:Sodium Bicarbonate; D000097623:Cefpodoxime