Hyoscine

Endpoint summary

Description of key information

The absorption, distribution, metabolism and excretion of scopolamine have been evaluated in numerous studies and summarized by Renner et al, in 2005*: 

In clinical trials, scopolamine was demonstrated to be absorbed by both the oral and dermal routes of administration. However, scopolamine undergoes significant first pass metabolism after oral administration and rapidly excreted, primarily in the urine, with an elimination half-life of approximately one hour. Oral bioavailability of scopolamine is about 13% where availability by the dermal route can be as high as 80%.

Scopolamine is biotransformed primarily via cytochrome P450 (CYP3A) mediated demethylation of the tropic acid alkyl chain and subsequent glucuronidation or sulfation. The metabolites of scopolamine are primarily excreted in the urine. Bioaccumulation is unlikely because of the rapid metabolism and excretion of scopolamine and its metabolites. As worst case an absorption rate of 100% for all routes is used for the assessment.

The toxicity of the scopolamine appears to be directly related to binding of the parent molecule to the muscarinic receptors of the peripheral and central parasympathetic nervous system. Metabolites of scopolamine have not been shown to be active in these receptors and do not appear to contribute to the toxicity of scopolamine. As a result, the toxic effects of scopolamine are predicted to be directly related to concentrations of the parent molecule at the target tissues.

In addition it is suspected that Scopolamine crosses the placenta readily.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Physical/Chemical Properties

Scopolamine is a moderate-size alkaloid molecule with a molecular weight of 303 g/mole and a pKa of 7.75 at 25°C (Chem ID Plus*). It is water soluble with a solubility of 29.82 g/L at 20°C, (key study, water solubility) and a partition coefficient (Log P_ow) of 1.31 at 20°C(key sudy, partition coefficient) . It is a solid at room temperature with a melting point of 70°C (key study, melting point) and thermally decomposes at temperatures above 140°C (key study, Stability). The vapor pressure of scopolamine is 1.5 x 10^-5Pa at 20°C (key study, vapour pressure). The median particle size L50(D (v,0.5) is 17µm corresponding to a medium dusty form.

With these phys/chem properties, absorption by both the dermal and oral absorption is likely as well as significant exposure by inhalation is likely.

Absorption

Oral 

Scopolamine possesses the phys/chem properties that favor absorption from the GI tract but bioavailability by the oral route is limited because of hydrolysis in stomach and extensive first pass metabolism.

 

According to the ECHA guidelines (2014) molecules with molecular weights of less than 500 g/mole are small enough to be candidates for absorption by passive diffusion from the GI tract. The molecular weight of Scopolamine is 303 g/mole which would favor its absorption from the GI tract. In addition, scopolamine is freely water soluble (29.82 mg/L) and has an octanol-water partition coefficient (log P_ow) of 1.31. This combination of both aqueous and lipid solubility also generally favors absorption by the oral route. On the other hand, scopolamine is an aminoalcohol ester and is susceptible to hydrolysis in the acid environment of the stomach (pH 2). While acid hydrolysis in the stomach has not been quantified, based on the structure it is likely to be substantial for orally-administered scopolamine. 

Clinical and animal data on the absorption of scopolamine after oral dosing are limited and the values are the result of a combination of absorption and first-pass clearance processes. Despite this, the available information indicates scopolamine is rapidly absorbed from the GI tract but ultimately has limited bioavailability. Ingestion of 0.5 mg scopolamine to healthy volunteers resulted in a maximum bioavailability of 13% (Renner et al, 2005*)[1]. Oral administration of 0.9 mg/kg scopolamine resulted in a maximum plasma concentration (C_max) of 2 ng/ml within one hour (McEvoy, 2008*). Ingestion of 0.5 mg/kg resulted in a C_maxof 0.54 ng/ml with the time to peak plasma concentration (T_max) of 23 minutes (Renne ret al 2005*). 

In addition, in a two-year oral gavage study with rats scopolamine hydrobromide trihydrate (CAS 6533-68-2), a close structural analog of scopolamine, serum levels of 12-28 ng/ml were achieved one hour after administration of 25 mg/kg by oral gavage (NTP 1997; key study carcinogenicity) indicating rapid absorption. 

Dermal 

Based on the phys/chem properties, scopolamine is likely to be absorbed after dermal application. According to the ECHA Guidelines (ECHA guidance chapter R.7c, 2014) molecules with molecular weights of less than 500 g/mole are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration. Materials with a water solubility of 100 mg/l and partition coefficients (log Pow) between 1 and 4 are also likely to be absorbed (ECHA guidance chapter R.7c, 2014). The molecular weight of scopolamine is 303 g/mole. It has a measured water solubility of 29.82 mg/L at 20°C and a log P_owof 1.31.  All of these factors would favor the dermal penetration of scopolamine.

 

Dermal absorption of scopolamine is well demonstrated in therapeutic applications with clinical studies. Transdermal dosing patches containing 1.5 mg scopolamine generate steady-state plasma concentration of approximately 100 pg/ml after eight hours (Muir and Metcalfe, 1983*). Other clinical trials have provided similar demonstrations of transdermal delivery of scopolamine (Renner et al, 2005*). Total bioavailability of scopolamine by the dermal route is difficult to estimate because of the competing absorption and elimination kinetics but is estaimated to be greater than 80% (Renner et al, 2005*).

Respiratory

The low vapor pressure (phys/chem properties) of scopolamine precludes significant absorption by inhalation. However, if scopolamine were aerosolized, either as dusts or in droplets, absorption across the respiratory epithelium would likely be rapid based on its partition coefficient and small molecular weight.  This is supported by clinical tests showing rapid absorption from an intranasal spray (Renner at al, 2005*). After administration of 0.4 mg scopolamine in a single intranasal spray, peak blood levels of 0.23 ng/mL were achieved 22 minutes after dosing with a total bioavailability of 83%.

Distribution

The distribution of scopolamine has not be fully characterized. Once absorbed, it reversibly binds to plasma proteins and is widely distributed in systemic circulation (Renner et al, 2005*). In a clinical study after IV or IM administration, the volume of distribution of scopolamine was estimated to be 360 L (Ebert et al, 2001*). This large volume of distribution is characteristic of material with significant protein binding and widespread distribution to tissues. 

Scopolamine has demonstrated effects on CNS function (CNS depression, drowsiness, reduction in REM sleep patterns) after administration by oral, dermal, or IV administration indicating it can cross the blood brain barrier (McEvoy, 2008*). It also likely crosses the placental barrier but there are no published reports characterizing this. 

Metabolism

Animal and clinical studies demonstrate scopolamine undergoes significant biotransformation, primarily in the liver, and is excreted in the urine (Renner et al, 2005*, McEvoy, 2008*). In vitro studies with rat liver microsomes show cytochrome P450-mediated oxidative demethylation resulting in the formation of –OH function on the alky group. This –OH function can be further transformed through conjugation with glucuronide or sulfate. This pathway is supported by in vivo studies reporting the presence of glucuronides and sulfate conjugates of scopolamine in the urine.  Both the P450 demethylation and the conjugation processes are saturable but the available clinical studies indicate that at pharmacologically-relevant doses, this metabolism occurs via first-order kinetics.

 

It is unlikely that the test substance is metabolized to more reactive (toxic) products. There is no evidence that the epoxide on parent molecule is unstable or subject to further metabolism to form reactive species and the amine function of the molecule likewise appears to remain stable. This assumption is supported by results from numerous in vitro and in vivo mutagenicity tests with intact metabolic activation systems (section 5.7. Mutagenicity). There was no significant increase in toxicity noted in the presence of metabolic activation systems making formation of reactive intermediates unlikely.

 

Excretion

The excretion kinetics of scopolamine and its metabolites have only been partially characterized. (McEvoy, 2008*). The primary route of excretion is urinary. After oral dosing, only a small fraction of the dose (4-5%) of the parent material was found in the urine. Excretion rates of free and total (free plus conjugated scopolamine) was reported to be 0.7 and 3.8mg/hr after administration of 1 mg from a transdermal patch. Elimination kinetics based on plasma concentrations after oral or IV administration indicate a half-life of 64-69 minutes (Renner et al, 2005*).  Bioaccumulation is unlikely because of the rapid metabolism and excretion of scopolamine and its metabolites.

Toxicodynamics

The biological effects of scopolamine are the result of a competitive antagonism of acetylcholine at muscarinic receptors (Renner et al, 2005*). Metabolites of scopolamine are inactive on these receptors. Thus, the biodynamic effects of scopolamine would be predicted from the concentration of the parent molecule at target tissues.

In clinical studies the clinical effects of scopolamine (alertness and EEG responses) correlated with plasma levels of scopolamine (Renner et al, 2005*) supporting the proposal that biological effects are related to delivered doses of parent scopolamine.

[1] Calculated by comparing the area under the curve for plasma concentrations and duration after oral administration with the area under the curve after IV administration – Bioavailability (F) = AUC_oral/AUC_IV. 

*Additional references toxicokinetics (not listet in 1. Annex of the CSR):

- Chem ID Plus (2016) Tox Net – CAS 51-34-3, United States Library of Medicine.

http:/chem.sis.nlm.nih.gov/chemidplus/rn/51-34-3 (accessed on Nov 11, 2016)

 

- Ebert U, Grossmann M, Oertel R, Gramatté T, Kirch W(2001) Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteersJ Clin Pharmacol. 41(1):51-60.

 

- McEvoy GK, ed. (2008) Scopolamine. Bethesda, MD: American Society of Health-System Pharmacists; 1323-1326. HSDB Reference (Peer Reviewed);

https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~IKbfgE:1

 

- Muir C, Metcalfe R. (1983) A comparison of plasma levels of hyoscine after oral and transdermal administration.J Pharm Biomed Anal. 1:363–367.

 

- Renner, UD, Oertel, R, Kirch, W (2005) Pharmacokinetics and Pharmacodynamics in Clinical use of Scopolamine. Therapeutic Drug Monitoring v27(5) 655-665.

https://chemm.nlm.nih.gov/countermeasure_scopolamine.htm#pubs