Bisphosphonates, bioavailability

When administered with ranitidine, alendronate bioavailability is increased. When calcium supplements or antacids are administered with risedronate or alendronate, absorption of the bisphosphonates is decreased, hi addition, risedronate absorption is inhibited when the drug is administered with magnesium and aluminum. There is an increased risk of gastrointestinal... 

The antiresorptive therapy of choice for hypercalcemia of malignancy is a bisphosphonate. Because of poor oral bioavailability, only intravenous agents should be used. 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Bisphosphonates are drugs of great interest in a number of metabolic bone diseases [119]. This therapeutic class comprises bis(phosphonic acids) and, more recently, bis(phosphonic acid) esters. The former are hydrophilic and poorly bioavailable, and they are generally not metabolized. In contrast, bis(phosphonic acid) esters may be more prone to biotransformation, as exemplified with the lead compound known as U-91502 (9.51 in Fig. 9.11). 

Bisphosphonates such as etidronate are often coprescribed with calcium supplements in the treatment of osteoporosis. If these are ingested concomitantly, the bioavailability of both is significantly reduced with the possibility of therapeutic failure. This may be avoided by allowing a sufficiently long dosage interval a possible approach is to give etidronate for 2 weeks and calcium supplements for 10 weeks in a 12-week period. 

Oral formulations are very poorly absorbed with bioavailability ranging from less than 1-6%. Doses should be taken on an empty stomach to improve absorption. Increasing the dose will lead to gastrointestinal complaints. Of the absorbed dose 20-50% is adsorbed to bone and only very slowly released. Free bisphosphonates are eliminated in the urine with an apparent half-live of about 20 hours. However, the elimination half-life of risedronic acid is more than... 

Bisphosphonates pamidronate and alendronate (the most active bisphos-phonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolyl-phenylalanyl-alendronate [Pro-Phe-alendronate (421)]. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport. ... 

All oral bisphosphonates have very limited bioavailability. They should be administered with a full glass of water following an overnight fast and at least 30 minutes before breakfast. They are excreted primarily by the kidneys and are not recommended for patients with a creatinine clearance of less than 30 mUmin. 

Bisacylphosphonates (50) and bishydroxyiminophosphonates (51) were found to be the first examples of non-geminal bisphosphonates biologically active in calcium metabolism disorders such as pathological calcification and bone resorption These compounds showed less toxic side-effects and improved bioavailability than bisphosphonates approved for clinical use. ... 

Estramustine bioavailability in 12 patients was inereased by about 80% when elodronate 800 mg four times daily was given with estramustine 280 mg twiee daily for 5 days. The serum levels and AUC of elodronate were not ehanged by estramustine. Doeumentation appears to be limited to this study. However, the effieaey and toxieity of estramustine should be monitored if elodronate is also given. The effeets of other bisphosphonates do not appear to have been studied. 

Haelters and co-workers have reported the synthesis of a series of new functionalized tetraethyl methylenebisphosphonates (105) with long chain aliphatic groups in order to increase their lipophilicity and bioavailability Subsequent allylation of the latter with allyl bromide afforded the corresponding bisphosphonates (106) (Scheme 35). The reactivity of the allyl group was further utilized to give access to other substituted bisphosphonates (107), functionalized by diverse groups including alcohol, aldehyde, carboxylic acid, epoxide and amine. 

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