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Absorption:

 

Oral:

In studies conducted using rats, dogs and humans, (Dudley et al. 1980a, b; Stevens et al. 1962, Resnick et al. 1990) the oral absorption of DTPA and DTPA salts appears to be very low, with an average intestinal absorption of 3 to 5% across all species.

 

Dermal:

There are no data available on the dermal absorption potential of DTPA, however in a risk assessment by the European Chemicals Bureau (2004), a structurally related chelating agent, EDTA was reported as having very low dermal penetration potential, with approximately 0.001% absorption through the skin. Considering the larger molecular weight of DTPA compared to EDTA it is believed that the dermal penetration of DTPA will be equally low, i.e. approximately 0.001%.

 

Inhalation:

There have been a number of studies of the effectiveness of administering aerosolised DTPA complexes to humans via the inhalation route. The substances investigated were various radionuclide complexes of DTPA such as111In-DTPA,99mTc-DTPA, Pu-DTPA and also the zinc and calcium salts of DTPA. These studies demonstrated that DTPA complexes are absorbed from the respiratory tract into the systemic circulation. The degree of absorption is however dependant on the site of deposition within the respiratory tract. Dudley et al. (1980b) demonstrated in dogs that the percentage of applied dose absorbed through the respiratory tract increases the further into the respiratory tract the dose is deposited. DTPA deposited high up in the respiratory tract was predominantly swallowed, with approximately 23% absorption from the nasopharyngeal region compared to approximately 90% absorption following instillation into the pulmonary region. A similar pattern was observed in rats (Stather et al. 1976, referenced in Dudley at al. 1980b). In humans, DTPA absorption following the administration of a nebulised spray containing DTPA was estimated to be 20% of the administered dose (Jolly et al. 1972). In this study the aerosol was inhaled through the mouth and mean droplet size was between 0.3 and 2 micro meters, making it more likely that droplets would travel more deeply into the respiratory tract, where absorption is more favourable.

 

Based on the available data it thus appears that absorption of aerosolised DTPA depends predominantly on the penetration of the droplets into the respiratory tract. The deeper the DTPA is deposited, the more likely it is that it will be absorbed. Considering the study by Jolly et al (1972) where a nebuliser was used to produce very small droplet sizes, it seems that a somewhat worst case estimate for absorption following exposure to an aerosol is approximately 20%. 

 

Exposure to DTPA is also possible via inhalation of the powdered form of the chelating agent. Therefore, considering the potential for absorption via the lung following exposure to inhaled powder, the potential for absorption will depend on the proportion of the inhaled powder that reaches the deeper lung, since much of the material that impacts higher up in the respiratory tract will be carried up into the mouth via the mucocilliary transport. Taking this into account, the ICRP (1994) reported that particles above 10μm are only partially inhaled. Some of the particles are sufficiently large not to be drawn in with an inspired breath (40%). Of the 60% inhaled, 50% are deposited in the extrathoracic air ways and only 10% enter the lung and result in a true inhalation dose. Therefore only 10% of the powder particles less than 10μm in diameter are available for absorption via the lungs, the remaining powder is either not inhaled or deposited higher up in the respiratory tract and eventually swallowed.

 

 

Distribution / Excretion:

 

Following exposure, the portion of the dose that is absorbed and thus available systemically is excreted via the urine very quickly. Intravenous administration of DTPA to man (Stevens et al. 1962) resulted in almost complete excretion via the urine within 24 hours, with a half life of approximately 2 to 4 hours. DTPA does not appear to become sequestered by any particular tissues, and in pregnant rats DTPA does not appear to pass into the fetal circulation (Zylicz et al 1975). Thus DTPA does not give rise to any concerns regarding bioaccumulation.

 

Following an oral dose, the unabsorbed material remains in the gastrointestinal tract and is excreted via the faeces. There appears to be little or no excretion of absorbed DTPA via the faeces (Stevens et al 1962).

 

 

Effect of DTPA on excretion of metals

 

There are many studies where the effects of administering DTPA to animals and man on the excretion of essential metals such as calcium, zinc, iron, manganese, magnesium etc. have been studied. Systemic administration of DTPA (intravenous, intraperitoneal, subcutaneous) causes as increased urinary excretion of zinc, calcium and to a lesser extent iron and manganese. The reason for the increase in the urinary excretion of certain metals following systemic exposure to DTPA is due to its formation of complexes with ‘free’ metals in the blood and lymph. These complexes are then excreted via the urine, carrying the metals out of the body.

 

DTPA has a high affinity for zinc and as such, zinc is one of the metals most affected by administration of DTPA. The increased excretion of zinc following prolonged administration of DTPA to humans has manifested as a zinc deficiency, treatable with supplementation of zinc sulphate, or administration of the zinc complex of DTPA.

 

The removal of metals from the body by DTPA is dependant on a number of factors:

 

1)     The dosing regime. Due to the short half life of DTPA in the body, a single dose is less effective at removing endogenous metals than multiple doses or a continuous transfusion.

2)     The availability of unbound or ‘free’ metals in the circulation. Due to the limited availability of ‘free’ zinc in the body, the dose of DTPA administered is not directly proportional to the amount of zinc excreted (Havliceket al. 1967). Small doses will bind more zinc per mole of chelant compared to larger doses.

3)     The presence of other metals in the circulation. DTPA has a strong affinity for zinc however it also binds manganese, calcium, iron, sodium, potassium. The presence of higher concentrations of these will therefore affect how much zinc is bound by DTPA

4)     The metal complex administered. Zinc complexes of DTPA are more stable and so less likely to cause an increase in excretion of metals. Sodium, Potassium and calcium salts do dissociate more easily and so the chelating agent is released and capable of chelating other metals, increasing their excretion/preventing their absorption