Pharmacokinetics

Following ingestion, ranitidine bismuth citrate dissociates in intragastric fluid, giving rise to ranitidine and soluble and insoluble forms of bismuth.

Absorption: Following a single oral 400-mg dose of TRITEC to healthy volunteers, mean (± SD) peak ranitidine plasma concentration of 455 (± 145.3) ng/mL occurred at 0.5 to 5 hours. The rate and extent of absorption of ranitidine derived from TRITEC increased proportionally with increasing doses up to 1,600 mg. Ranitidine plasma concentrations showed no evidence of accumulation during a 28-day dosing period.

Oral absorption of bismuth is variable. A mean (± SD) peak bismuth plasma concentration of 3.3 (± 2.0) ng/mL occurs at 15 to 60 minutes after a 400-mg dose. The rate and extent of absorption of bismuth from TRITEC do not increase with increasing doses up to 800 mg, but increase more than proportionally with increasing doses above 800 mg. The rate of absorption of bismuth derived from an 800-mg dose of TRITEC is decreased by 50%, and the extent of absorption is decreased by 25% when taken 30 minutes after a meal as compared to 30 minutes before a meal. The absorption of bismuth from an 800-mg dose of TRITEC increased when gastric pH exceeded 6. The increased pH resulted from the administration of an 800-mg dose of TRITEC given 3 hours previously. Mucosal penetration and absorption of bismuth from TRITEC are not affected by the degree of gastritis, the presence of Helicobacter pylori, or an active ulcer. Small amounts of bismuth accumulate in plasma during twice-daily dosing with TRITEC. In a 28-day study at 800 mg b.i.d. (twice the recommended daily dose), peak bismuth concentrations did not exceed 20 ng/mL at any time in any patient, with a median peak concentration of 6.3 ng/mL on day 28. Median peak and trough concentrations on day 28 were 105% and 68% of predicted steady-state peak and trough concentrations. In a study at 400 mg b.i.d. for 12 weeks (three times the recommended duration), trough bismuth concentrations did not exceed predicted accumulation in any patient, with a median trough concentration of 2.8 ng/mL at week 12.

Distribution: The volume of distribution for ranitidine is 1.7 L/kg. Serum protein binding of ranitidine averages 15%. Bismuth is 98% bound to human plasma proteins, primarily albumin.

Metabolism: Ranitidine is metabolized to the N-oxide, S-oxide, and N-desmethyl metabolites, accounting for approximately 4%, 1%, and 1% of the dose, respectively. It is not known whether bismuth undergoes any biotransformation.

Excretion: The elimination half-life of ranitidine derived from TRITEC is 2.8 to 3.1 hours. The principal route of elimination for ranitidine is renal, accounting for 30% of the dose. Renal clearance averages 530 mL/min, indicating active tubular secretion. Total clearance is 760 mL/min. Elimination of bismuth is polyexponential, with a terminal elimination half-life of 11 to 28 days. Bismuth has an average renal clearance of 30 to 60 mL/min, indicating net tubular secretion. Less than 1% of bismuth derived from TRITEC is recovered in urine after oral administration. Up to 28% of bismuth was recovered in the feces during a 6-day postdose period. Bismuth also undergoes minor excretion in the bile.

Special Populations

Geriatric: Clinically insignificant increases in plasma concentrations of ranitidine were observed in elderly patients. Bismuth concentrations may be elevated in elderly patients as a result of decreased renal elimination.

Pediatric: No information on the pharmacokinetics of ranitidine or bismuth derived from TRITEC was obtained in this population.

Gender: There is no evidence of a difference in the pharmacokinetics of ranitidine between males and females when adjusted for body weight. There is no difference in the extent of absorption of bismuth when adjusted for body weight; significant differences are observed for peak bismuth plasma concentrations in healthy females.

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