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Transcript
Urine Color Test for the Detection Phenothiazine of Compounds Irene S. Forrest and Fred M. Forrest N PREVIOUSLY REPORTED urinary color tests for chlorproinazine, promazine, and mepazine (1, 2) a test solution containing ferric chloride in dilute sulfuric acid was mixed with the urine sample, and the color reaction resulting from the respective drug metabolite and the test solution was immediately read against prepared color charts. These reactions were specific for the indicated drugs which, in psychiatric hospital practice, are administered in daily doses usually ranging from 100 to several thousand milligrams. In testing for the more recently developed drugs containing either a piperazinyl group such as prochlorperazine (Compazine), perphenazine (Trilafon), thiopropazate (Dartal), their trifluoromethylated derivatives Stelazine and Prolixin, or trifluoropromazine (Vesprin), and for smaller amounts (less than 100 mg. per day) of chlorpromazine (Thorazine), promazine (Sparine), or mepazine (Pacatal), a more sensitive reagent for this entire group of compounds was devised. This new test solution consists of 5 parts of 5 per cent ferric chloride, 45 parts of 20 per cent perchioric acid, and 50 parts of 50 per cent nitric acid (subsequently referred to as FPN). This test solution produces immediate color reactions with the urines of patients who have ingested any phenothiazine compound, including the various antihistaminic compounds of this group. In this test, 1 ml. of FPN test solution is mixed with 1 ml. urine. In the lowest phenothiazine levels, corresponding to drug intakes of 5 to 20 mg. per day, the yellow urine color turns to a light pinkish-orange, while From tIme Research Laboratory and Acute Service, Brockton, Mass. Development of this test was carried out witim funds Squibb & Sons which is gratefully acknowledged. Veterans Administration froma a research grant Hospital, from E. R. 12 FORREST & FORREST Clinical Chemistry daily drug doses of 25 to 70 mg. produce reactions in various shades of pink. Drug doses of 75 to 120 mug. daily yield increasingly intense shades of violet, while doses of 125 rug, and more are reflected by deep purple reactions of increasing opaqueness and inklike appearance. The color chart (Fig. I) illustrates the drug concentration range and the color developed upon addition of the reagent. The stability of these color reactions varies from a minimum of about 10 sec. for the lowest drug doses up to 30 mg., to 20 to 30 sec. for the medium range of doses up to 73 mg., and up to several minutes for the higher drug doses. While FPN reagent does not yield the optimum scale of color development for each of the individual drugs tested, it proved useful as a general group reagent, indicating absence or presence of phenothiazine compounds and allowing a rough estimate of quantity of drug ingested. In patients on continuous administration of phenothiazine drugs, any urine specimen is suitable for the test. In the case of extremely small daily doses of below 20 mg., or in the case of administration of a single small dose, the period of between 2 and 5 hours after administration is the optimum testing time. SENSITIVITY OF THE FPN REACTION From simultaneously undertaken studies on the excretion period of phenothiazine compounds* in psychiatric patients after discontmuation of administration, we found by means of this and other sensitive, specific reactions that urinary excretion extends over a period of more than 12 weeks rather than the 4 to 7 days indicated in the literature (3, 4). After a single dose of 10 mg. of a phenothiazine drug, this test on 1 ml. of urine, carried out between 2 and 5 hours after drug administration, shows a distinct pink reaction. From parallel quantitative determinations according to a modification of the method indicated by Salzman and Brodie (5) we know that 1 ml. of urine in this instance contains less than 1 g. of sulfoxide, the major metabolite, which does not yield a color reaction. Therefore, there seems to be present, in addition to the sulfoxide, an appreciable amount of other metabolites,t responsible for the color reaction. Thus a fraction of a microgram of intermediary drug metabolite is demonstrable by FPN. * Study now in progress tA quantitative of their metabolites in this method for is currently hospital. the determination being developed. of urinary phenotimiazine drugs and all Vol. 6, No. I, 1960 DETECTION + ++ 5-20 mg. 20-70 mg. Fig. 1. Color chart the test, add 1 nil. FPN mixture in the test tube test. A Shades higher chloride OF PHENOTHIAZINE for urine test +++ for 70-120 mg. small amounts 13 COMPOUNDS of phenothiazimme ++++ 120 mg. & over drugs. To performn test solution to 1 ml. urine, mix gently, and match the color of the against tIme clmart. Read within 20 sec. No color indicates a negative slight darkening without formation of pink or violet shades is considered negative. of violet darker than indicated for the --f-}--jlevel represent correspondingly concentrations of drug. The FPN test solution is composed of 5 ml. 5% ferric solution, 45 ml. 20% perchloric acid, and 50 ml. 50% nitric acid. 14 FORREST & FORREST RELIABILITY OF TEST AND POTENTIALLY Clinical Chemistry INTERFERING FACTORS In more than 1500 urine specimens tested, we have seen no false negatives. In extremely dilute specimens (after fluid intake of more than 3 L. per day) and a testing time of more than 5 hours after drug administration, a false negative might result, however. All other apparently false negative tests could be traced to the patients’ failure to ingest the medication. (With regard to the problem of psychiatric patients “cheeking” the drugs, see Refs. 1, 2, 6, 7, 8, and 9.) We have seen between 1 and 2 per cent false positives in approximately 500 control urine tests of patients and personnel in the absence of phenothiazine drugs. All but one could be traced to elevated urinary levels of bile metabolites, particularly urobilinogen, which yields similar color reactions with FPN. Thus in patients with impaired liver function, this test can not be uncritically applied. Nonphenothiazine-derived drugs-e.g., reserpine, barbiturates, ineprobamate, the various energizers, and vitamins-did not show any color development with the reagent, nor did they interfere with the test. Color reactions similar to those obtainable with FPN are obtained with 50 per cent nitric acid as the test solution. However, the resulting color tests are very unstable and actually fleeting at low drug levels, a fact which complicates their evaluation. Similar difficulties were encountered in the method of Neve (7), who uses a mixture of nitric acid and sodium nitrite solution as test reagent. While FPN is a sensitive group reagent for all phenothiazine compounds that permits a rough conclusion on the total quantity of such drugs present in urine, no conclusion with regard to the specific drug or mixture of drugs can be drawn. Some of the more recently introduced drugs derived from phenothiazine show optimum color development suitable for semiquantitative readings against color charts with different reagents. Rapid urinary tests for these individual drugs and their optimum reagents (various heavy-metal salts in concentrated hydrochloric acid), with pertinent color charts, have been reported by us (8, 9). In view of the above-mentioned protracted urinary excretion time after discontinuation of long-term drug administration, it should be considered that any urinary drug level may result from a recently ingested small dose, or from a high dose possibly preceding the test by several weeks. Hence it is not possible to determine by a single (e.g., pink) FPN reaction whether a patient took, for instance, 20 Vol. 6, No. I, 1960 DETECTION OF PHENOTHIAZINE mg. of a drug on the day of the test, 800 mg. 2 weeks before. 15 COMPOUNDS 75 mg. on the previous day, REFERENCES 1. 2. Forrest, Forrest, F. M., and Forrest, I. S., Am. J. Psychiat. 113, 931 (1957). F. M., Forrest, I. S., and Mason, A. S., Am. J. Psychiat. 114, 3. 4. 5. 6. 7. 8. 9. Citterio, Fedorov, Salzman, Pollack, Neve, H. Forrest, Forrest, C., Lay. N. A., N. P., B., Am. K., J. F. M., F. M., 931 Neuropsychiat. 20/2, 201 (1957). and Shnol, S. E., Zh. Nevropat. Psikhiat. 56, 139 (1956). amid Brodie, B. B., J. Pharin. 4. Exp. Ther. 118, 56 (1956). J. Psychiat. 115, 77 (1958). Ment. Sc. 104, 488 (1958). Forrest, I. 5., and Mason, A. S., Ani. J. Psychiat. 115, 1114 Forrest, I. S., and Mason, A. S., Am. J. Psychiat. 116, 549 (1958). (1959). (1959). or