The Pharmacokinetics and Pharmacodynamics of Iron Preparations

Abstract

Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3–4 weeks. Accordingly, serum iron concentration and area under the curve (AUC) are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III)-hydroxide complexes with carbohydrate ligands or orally as iron(II) (ferrous) salts or iron(III) (ferric) complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia.

Pharmacokinetic Interactions between Intravenous Ciprofloxacin and Oral Ferrous Sulfate

“…Interestingly, the reduced activity in plasma was more noticeable after oral ferrous sulfate administration. The time frame of shift in activity observed approximates the absorption profile of iron reported in a previous study in which maximum plasma iron concentration is achieved at approximately 2 hour in rats after administration of oral ferrous sulfate (Geisser and Burckhardt, 2011). Therefore, the impact of iron on the pharmacokinetics of ciprofloxacin was more apparent during terminal elimination of the antibiotic, when the potential for formation of chelates in the systemic circulation was highest.…”

The Complete Study of the Switch from Iron-Sucrose Originator to Iron- Sucrose Similar and Vice Versa in Hemodialysis Patients

“…Variations in complex structure and stability are likely to have accounted for the differences in Hb control, since the kinetics of iron dissociation influence the pattern of iron release, distribution and storage [16]. In this population of iron-deficient individuals, TSAT values decreased dramatically after the switch, indicating that less iron was available for erythropoiesis.…”

“…It has previously been observed that the administration of I.V. iron carbohydrate complexes with low stability, such as sodium ferric gluconate, can result in severe and extended parenchymal liver necrosis secondary to iron-induced lipid peroxidation in nonclinical models [16] and the high level of total bilirubin and low TSAT seen in the current clinical trial, during period 4 with the use of ISS, are consistent with some degree of hepatic toxicity and less stable molecular structures in the ISS preparations [38]. The significant increase in serum iron and TSAT described in the experimental study from Toblli [39,40], coupled with greater iron deposition, indicated more rapid release of iron compared to IS due to overloading of serum transport proteins.…”

“…The degree of stability of iron carbohydrate complexes is critical, since weakly bound iron may dissociate from the complex and catalyze the generation of reactive oxygen species. Stability is highly dependent on the manufacturing process [16].…”

Iron Therapy Challenges for the Treatment of Nondialysis CKD Patients

“…form; thus, dietary ferric iron is reduced to the ferrous form to be absorbed (67). Prescribed oral iron salt preparations are in the ferrous form, including ferrous sulfate, ferrous fumarate, ferrous gluconate, and polysaccharide iron complex (68).…”