Effects of calcium and lipophilicity on transport of clodronate and its esters through Caco-2 cells

Raiman, Johanna; Niemi, Riku; Vepsäläinen, Jouko; Yritys, Kirsi; Järvinen, Tomi; Mönkkönen, Jukka

doi:10.1016/s0378-5173(00)00655-4

Cited by 17 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, bisphosphonates are capable of binding divalent metal ions such as Ca 2 + , Mg 2 + and Fe 2 + with high affinity, further diminishing intestinal absorption [9]. These chemical modifications could further diminish the high avidity of bisphosphonates for Ca 2 + [27], and consequently decrease their bone uptake and increase their soft tissue-targeting properties. These chemical modifications could further diminish the high avidity of bisphosphonates for Ca 2 + [27], and consequently decrease their bone uptake and increase their soft tissue-targeting properties.…”

Section: Discussionmentioning

confidence: 99%

A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice

Ledoux¹,

Hamma-Kourbali

Benedetto

et al. 2006

Anti-Cancer Drugs

View full text Add to dashboard Cite

Bisphosphonates are extensively used in the treatment of patients with metastasis-induced osteolysis. The major drawback in the efficacy of all bisphosphonates lies in their high hydrophilic nature, which results in poor membrane permeability and low availability for soft tissues. A reasonable approach to overcome these problems consists in masking one or more ionizable groups of bisphosphonates, notably by esterification of the hydroxyl functions. We have previously shown that the novel non-nitrogen-containing bisphosphonate BP7033 inhibited angiogenesis and growth of primary tumors in nude mice. The present study focuses on the dimethyl-esterified analog of this compound (Me-BP7033). In-vitro, Me-BP7033 inhibited proliferation of human carcinoma A431 cells as well as their invasive activity based on a transwell invasion assay. in-vivo, administration of Me-BP7033 (0.3 mg/kg) twice a week for 5 weeks inhibited the tumor growth of A431 cells xenografted in nude mice by 65%. Immunostaining of endothelial cells (ECs) in tumor sections revealed that Me-BP7033 inhibited the intratumor ECs density by 60%. The in-vivo anti-angiogenic properties of Me-BP7033 were also demonstrated in an in-vivo angiogenesis assay showing that Me-BP7033 reduced the vascular endothelial growth factor-stimulated infiltration of ECs in a Matrigel plug by 70%. In summary, we demonstrated for the first time that a diesterified bisphosphonate exhibited in vivo both anti-tumoral and anti-angiogenic activities with no apparent sign of toxic effects. These new diesterified compounds, which could display enhanced bioavailability and pharmacokinetics, thus represent interesting candidates for therapeutic applications such as cancer treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice

Ledoux¹,

Hamma-Kourbali

Benedetto

et al. 2006

Anti-Cancer Drugs

View full text Add to dashboard Cite

show abstract

“…The poor absorption of the bisphosphonates from the GI lumen is probably due to their polarity, being negatively charged at physiological pH 57 , 58 . The polarity of the bisphosphonates hinders transcellular transport through epithelial membranes, and paracellular transport is thought the likely route of absorption 57 – 61 . The predominant site of absorption of alendronate is in the upper part of the small intestine 57 .…”

Section: Pharmacokineticsmentioning

confidence: 99%

Ibandronate: A Clinical Pharmacological and Pharmacokinetic Update

Barrett

Worth

Bauss

et al. 2004

The Journal of Clinical Pharma

135

123

View full text Add to dashboard Cite

Ibandronate is a potent nitrogen-containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and Paget's disease. Oral ibandronate is rapidly absorbed (t(max) < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%-50%) and through renal clearance (CL(R) approximately 60 mL/min). The CL(R) of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (V(D) > 90 L) results in a multiphasic elimination (t((1/2)) range approximately 10-60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between-dose intervals.

show abstract

“…021) × 10 −7 cm/s ( n = 9). Such a low permeability coefficient indicated alendronate transport via the paracellular pathway, as for other bisphosphonates [18,19] . All the micelles and microemulsions promoted the transport of alendronate with a dilution‐dependence.…”

Section: Resultsmentioning

confidence: 92%

“…Such a low permeability coefficient indicated alendronate transport via the paracellular pathway, as for other bisphosphonates. [18,19] All the micelles and microemulsions promoted the transport of alendronate with a dilution-dependence. The number in the bracket indicates the enhancement ratios versus solution (1 mm alendronate).…”

Section: Effect Of Microemulsions and Micelles On Alendronate Transpomentioning

confidence: 99%

Positively-charged microemulsion for improving the oral bioavailability of alendronate: in-vitro and in-vivo assessment

2011

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

Effects of calcium and lipophilicity on transport of clodronate and its esters through Caco-2 cells

Cited by 17 publications

References 21 publications

A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice

A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice

Ibandronate: A Clinical Pharmacological and Pharmacokinetic Update

Positively-charged microemulsion for improving the oral bioavailability of alendronate: in-vitro and in-vivo assessment

Contact Info

Product

Resources

About