Phenylephrine hydrochloride

Endpoint summary

Additional information

In the National Toxicological Program, Technical Report Series No. 322. Toxicology and carcinogenesis studies of phenylephrine hydrochloride (CAS No. 61 -76 -7) in F344/N rats and B6C3F1 mice (feed studies) a summary on the absorption, distribution, metabolism and excretion of phenylephrine hydrochloride is presented. This information together with the available physical chemical properties is used to describe the toxicokinetics of phenylephrine hydrochloride.

1) UPTAKE

Oral:

The relatively low molecular weight of 203.7 g/mol suggests rapid up-take of phenylephrine hydrochloride since it may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. On the other hand, the low log Pow value (-3) does not favor absorption. Nonetheless, according to Bogner and Walsh (1964), phenylephrine hydrochloride is absorbed after oral administration. Furthermore, in the long-term (2-year) study performed by the NTP (1987) repeated exposure via the diet resulted in effects on the liver and prostate and, possibly the lung, in rats (in the affected organs the incidence of inflammation was increased), and the liver (increased incidence of focal cellular change) in mice. These effects occurred from the lowest dose levels tested, namely 620 mg/kg diet in rats (22 and 26 mg/kg bw/day in males and females, respectively) and 1250 mg/kg diet in mice (130 and 140 mg/kg bw/day in males and females, respectively). In the 12-week feeding studies preceding the 2-year studies dietary levels up to 20,000 mg/kg feed were tested. At these higher doses growth retardation (from 1,250 mg/kg feed in rats and mice) and mortality (from 5,000 g/kg feed in rats and 10,000 mg/kg feed in mice) occurred. These observations indicate that phenylephrine hydrochloride is absorbed via the oral route.

 

Inhalation:

No experimental data is available concerning the absorption of phenylephrine hydrochloride via inhalation. However, for highly hydrophilic substances uptake may be limited by the low rate at which they partition out of the mucus and into the blood. It is more likely that inhaled phenylephrine hydrochloride is retained in the mucus and transported out of the respiratory tract. Nonetheless, according to Ibrahim et al. (1983) and Meyer and Fraunfelder (1980) phenylephrine hydrochloride is rapidly absorbed following inhalation of nasal sprays.

Dermal:

No experimental data is available concerning the absorption of phenylephrine hydrochloride via the skin. The high water solubility (1000 g/l) and the very low log Pow (-3) indicate that dermal up-take of the compound will probably be low.

2) DISTRIBUTION

No specific statement can be made regarding the distribution of phenylephrine hydrochloride in organisms. However, the effects observed as described above indicate that distribution of phenylephrine hydrochloride occurs in the body.

 

3) METABOLISM

Phenylephrine is thought to undergo oxidative deamination by monoamine oxidase to the aldehyde. The aldehyde can be further oxidized by aldehyde oxidase to meta-hydroxymandelic acid or reduced by aldehyde dehydrogenase to meta-hydroxyphenylglycol. In a study in male Wistar rats where intraperitoneal injections of tritiated phenylephrine were given, 72% of the label was collected in the urine within 24 hours. Sixteen percent of the dose was unconjugated phenylephrine, the sulfate conjugate, or the glucuronide conjugate. Approximately 56% of the dose was found as meta-hydroxymandelic acid (6%), meta-hydroxyphenylglycol (50%), or their sulfate or glucuronide conjugates (Ibrahim et al., 1983). The general pattern of metabolism is similar in humans except that approximately 60% of an inhaled or orally ingested dose of phenylephrine appears in the urine within 24 hours as unchanged or conjugated phenylephrine, 30%-35% of the dose appears as meta-hydroxymandelic acid or its conjugates, and 8%-9% appears as meta-hydroxyphenylglycol or its sulfate or glucuronide conjugates (Ibrahim et al.,1983).

4) ACCUMULATION

As mentioned above the test substance is metabolized and it is therefore not expected that it accumulates in organisms. The high water solubility and the very low Log Pow also indicate that accumulation of the compound once taken up will be low. Further, the generally short duration of action (20 minutes following intravenous injection (Gilman et al, 1985) suggests a rather rapid distribution, metabolism and excretion.

5) EXCRETION

As indicated above, the major route of excretion is via the urine. No data is available on possible excretion by other processes. Its low molecular weight implies that excretion by bile will probably not occur.

References:

- Bogner RL, Walsh JM (1964) Sustained-release principle in human subjects utilizing radioactive techniques. J. Pharm Sci. 53:617-620.

- Gilman A, Goodman LS, Rall TW, Murad F, Eds. (1985) Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 7th ed. New York: Macmillan Publishing Co., pp. 145-180.

- Ibrahim KE, Midgley JM, Crowley JR, Williams CM (1983) The mammalian metabolism of R-(-)-m-synephrine. J. Pharm. Pharmacol.35(3):144-147.

- Meyer SM, Fraunfelder FT (1980) 3. Phenylephrine hydrochloride. Ophthamology 87(11):1177-1180.

- National Toxicological Program, Technical Report Series No. 322. Toxicology and carcinogenesis studies of phenylephrine hydrochloride (CAS No. 61 -76 -7) in F344/N rats and B6C3F1 mice (feed studies).