Plasma protein binding of APD: Role of calcium and transferrin

Daley‐Yates, Peter T.; Cal, J. C.; Cockshott, A.R.; Pongchaidecha, Manat; Gilchrist, K.

doi:10.1016/0009-2797(92)90028-j

Cited by 11 publications

(15 citation statements)

References 12 publications

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“…The effect of serum on binding was investigated next since in vivo bone binding is expected to take place in the presence of serum constituents capable of competing for mineral binding (e.g., serum proteins and other cations such as Ca 2+ ) 27. The binding in the presence of serum was evaluated by the FITC‐labeled PLL, since serum interfered with the TNBS assay (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

The Interaction of Cationic Polymers and Their Bisphosphonate Derivatives with Hydroxyapatite

Zhang

Wright

Ozber

et al. 2007

Macromolecular Bioscience

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Conjugating proteins with bisphosphonates (BPs), a class of molecules with exceptional affinity to hydroxyapatite (HA), is a feasible means to impart bone affinity to protein-based therapeutic agents. To increase the targeting effectiveness while minimizing protein modification, a polymeric linker containing multiple copies of BPs could be constructed for protein conjugation and targeting to bone. Towards this goal, poly(L-lysine) (PLL) and poly(ethylenimine) (PEI) were utilized as the polymeric backbones to incorporate a BP, namely 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (thiolBP), by using N-hydroxysuccinimidyl polyethylene glycol maleimide and succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, respectively. In vitro and in vivo mineral affinity of the polymer-BP conjugates were determined in comparison with the unmodified polymers. The in vitro results indicated strong binding of the cationic polymers to HA in their unmodified form. BP conjugation did not enhance the inherent mineral affinity of the polymers; in contrast, certain modifications negatively affected the polymers' binding to the HA. In vivo results from a subcutaneous implant model in rats also showed no significant difference in mineral affinity of the BP modified and unmodified PEI. We conclude that thiolBP conjugation to the cationic polymers PLL and PEI was not beneficial for increasing the mineral affinity of the polymeric molecules. The strong interaction between the cationic polymers and HA may make the polymers suitable for imparting mineral affinity to bone-acting therapeutics.

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Section: Resultsmentioning

confidence: 99%

The Interaction of Cationic Polymers and Their Bisphosphonate Derivatives with Hydroxyapatite

Zhang

Wright

Ozber

et al. 2007

Macromolecular Bioscience

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“…Otherwise, the protein preparations derivatized by sulfoSMCC alone, without conjugation to a thiolated BP, would have exhibited a high affinity to HA. The fact that a strong HA affinity was obtained in serum and not simply in an artificial buffer medium is critical, because in vivo bone mineral binding is expected to take place in the presence of serum constituents which might bind to bisphosphonates (such as Ca 2+ and transferrin (30, 31)). The serum proteins will additionally compete with BP conjugates for bone mineral binding, and as shown here, it was essential to retain conjugate binding in the presence of such a “background”.…”

Section: Discussionmentioning

confidence: 99%

Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

et al. 2000

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Growth factors are endogenous proteins capable of stimulating new bone formation, but their clinical benefit for systemic stimulation of bone mass has not been demonstrated. The critical challenge is to deliver a significant dose of the proteins to bone after intravenous injection. This challenge may be overcome by derivatizing proteins with ligands that exhibit a high bone affinity (e.g., bisphosphonates). To demonstrate the feasibility of this approach, 1-amino-1,1-diphosphonate methane (aminoBP) was conjugated to a model protein, albumin. The conjugation was performed by (1) converting the amino group of aminoBP to a thiol group using 2-iminothiolane, (2) derivatizing the albumin amino groups with a thiol-reactive sulfosuccinimidyl-4-(N-maleimidomethyl)-1-cyclohexane carboxylate, and (3) reacting the derivatized albumin with thiolated aminoBP. Typically, 1-4 aminoBP molecules per albumin were obtained. The conjugated albumin exhibited a high affinity to hydroxyapatite that was proportional to the extent of conjugation. The conjugates were shown to exhibit a high affinity to bone matrix in vitro in a serum-containing medium. Once bound to bone matrix, the conjugates were found to desorb more slowly than the unmodified albumin, especially from bone whose organic matrix was removed by ashing. In conclusion, conjugation of bisphosphonates to albumin was shown to impart a high bone affinity to the protein, and such conjugates can be potentially targeted to bone.

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“…Plasma proteins also appear to bear some influence. A 30.2% plasma binding has been described for pamidronate [22], probably to globulin fractions and transferrin. The correlation between t,/213 and 13-fraction of plasma proteins seems to indicate that something similar happens with olpadronate.…”

Section: Discussionmentioning

confidence: 99%

Serum kinetics, bioavailability and bone scanning of 99mTc-labelled sodium olpadronate in patients with different rates of bone turnover

Degrossi¹,

Ortiz²,

Degrossi³

et al. 1995

Eur J Clin Pharmacol

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The activity of olpadronate labelled with technetium-99m(99mTc) was monitored in plasma and urine samples after single oral (925 MBq 99mTc/10 mg, coadministered with 50 mg cold drug) and intravenous (925 MBq 99mTc/5 mg) administrations to two groups of patients with different rates of bone turnover. The first group comprised high bone turnover (HBTO) patients suffering from Paget's bone disease; the second group comprised patients with normal to low bone turnover (NBTO) having the diagnosis of rheumatoid arthritis and secondary osteoporosis. Kinetic variables were correlated with anthropomorphometric variables, biological markers of bone metabolism and plasma proteins. Data were also obtained after repeatedly dosing the HBTO patients. Additionally, Paget's bone and healthy bone (PB/HB) uptake before and after low-dose oral treatment were assessed by means of scintigraphy. Results showed that most of the kinetic variables did not differ between the two groups of patients, except for a greater Vss and smaller blood area under the curve AUC in the patients with HBTO. After a repeated-dose administration period, the blood AUC activity and Whole Body Retention (WBR) of the HBTO patients tended to be similar to those of the NBTO patients. In both groups, after oral dosing, the Cmax was 20 times lower than the C0.5 after i.v. injection, and the oral bioavailability ranged from 3% to 4%. Finally, the plasma t1/2 beta ranged from 9 to 14 h. Correlation coefficients were obtained from multiple regression analysis; kinetic variables showed very low correlations with anthropomorphometric measurements. In contrast the Vss and WBR were significantly correlated with serum alkaline phosphatase levels and the Vss also with urine hydroxyproline levels. Plasma protein concentration was also correlated with excretion parameters such as CLP and plasma t1/2 beta after an oral dose. Scintigraphic studies in the HBTO group allowed bone selectivity to be seen through skeletal drug uptake. The 15 Pagetic lesions analysed in the HBTO group showed a decrease in PB/HB ratio from 3.8 in the basal study to 2.7 after olpadronate administration for 30 days at the rate of 50 mg/day. In conclusion, the kinetic profile of 99mTc-labelled olpadronate, mainly AUC and WBR, showed a dependence upon bone metabolism and seemed unrelated to body size variables. HBTO patients showed a lower blood AUC but a higher Vss. Both variables may have been reflecting the fact that the drug binds selectively with calcified tissues and, in turn, with the target compartment. Scintigraphy confirmed the labelled-compound bone selectivity as a desirable feature for a bone-scanning agent.

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Plasma protein binding of APD: Role of calcium and transferrin

Cited by 11 publications

References 12 publications

The Interaction of Cationic Polymers and Their Bisphosphonate Derivatives with Hydroxyapatite

The Interaction of Cationic Polymers and Their Bisphosphonate Derivatives with Hydroxyapatite

Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

Serum kinetics, bioavailability and bone scanning of 99mTc-labelled sodium olpadronate in patients with different rates of bone turnover

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