Pharmacokinetics

Phenylpropanolamine is readily and completely absorbed, but pseu-doephedrine, with a bioavailability of only approx 38%, is subject to gut wall metabolism, and absorption may be erratic (69). Pure ephedrine is well absorbed from the stomach, but absorption is much slower when it is given as a component of ma huang, rather than in its pure form (70). Ephedrine ingested in the form of ma huang has a tmax of nearly 4 hours, compared to only 2 hours when pure ephedrine is given. Like its enantiomers, ephedrine is eliminated in the urine largely as unchanged drug, with a half-life of approx 3-6 hours.

The rate at which any of the enantiomers is eliminated depends upon the urinary pH. At high pHs, excretion time is prolonged. At low pH ranges, excretion is accelerated. In controlled laboratory studies, where volunteer subjects were given either bicarbonate or ammonium chloride, the higher the urine pH, the more slowly the ephedrine and pseudoephedrine were excreted. Conversely, when the urine pH is low, excretion is accelerated (71). The importance of these observations is hard to assess, because without the addition of bicarbonate, urine pH values in the general population rarely approach 8.0. A study of pseudoephedrine pharmacokinetics in 33 volunteers who were not treated with drugs to alter urine pH found that these parameters could not be correlated to urine pH, mainly because there was little difference in pH between the different participants (72). Excretion patterns may be much more rapid in children, and a greater dosage may be required to achieve therapeutic effects. Patients with renal impairment are at special risk for toxicity.

Peak concentrations for the other enantiomers, specifically phenylpropanolamine and pseudoephedrine, occur earlier (0.5 and 2 hours, respectively) than for ephedrine, but all three drugs are extensively distributed into extravas-cular sites (apparent volume of distribution between 2.6 and 5.0 L/kg). No protein-binding data in humans are available. Peak ephedrine levels after ingestion of 400 mg of ma huang, containing 20 mg of ephedrine, resulted in blood concentrations of 81 ng/mL—essentially no different than the peak ephedrine levels observed after giving an equivalent amount of pure ephedrine (70,25). In another study, 50 mg of ephedrine given orally to six healthy, 21-year-old women produced mean peak plasma concentrations of 168 ng/mL, 127 min after ingestion, with a half-life of slightly more than 9 hours (73). The results are comparable to those obtained in studies done nearly 30 years earlier (74).

Very high levels of methylephedrine have been observed in Japanese polydrug abusers taking a cough medication called BRON. Concentrations of methylephedrine less than 0.3 mg/L, the range generally observed in individuals taking BRON for therapeutic rather than recreational purposes (75), appear to be nontoxic and devoid of measurable effects. Methylephedrine is a minor component of most ephedra plants, but in Japan (where, unlike in the United States, methylephedrine is legally sold) it is produced synthetically, and is used in cough and cold remedies, especially BRON (76-78). In terms of catecholamine stimulation, methylephedrine appears comparable to ephe-drine; however, it does not react with most standard urine screening tests for ephedrine (75). This can be a cause of some forensic confusion, because 1015% of a given dose of methylephedrine is converted to ephedrine (75).

Although the issue has been raised in litigation, the amounts of methylephedrine and norephedrine contained in naturally occurring ephedra are so low as to be of no clinical consequence. For example, the study by Gurley et al. found that most of the commercial products tested had no methylephedrine whatsoever, but when it was present, it was usually in quantities of less than 1 mg per serving (range 0.2 to 2.2 mg). If the volume of distriution (Vd) of methylephedrine is assumed to be 3.5, approximately the same as ephedrine, then a 70-kg man ingesting a 2-mg serving of methylephedrine would produce a blood concentration of (dose = kg weight x blood concentration x Vd) 0-0.06 mg, undoubtedly below most laboratories' minimum level of detection, and a clinically insignificant finding. Similar considerations apply to the small amounts of norephedrine found in these products.

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