Urine drug screening results from volunteers in phase I clinical pharmacology studies: are we being misled?

The general intent of phase I clinical pharmacology studies is to demonstrate the safety and tolerability of investigational new drugs in healthy human volunteers. There is emerging evidence that people who volunteer for these studies are not always truthful with investigators during the screening process. All healthy volunteers who participate in studies at the SmithKline Beecham Clinical Pharmacology Unit in Philadelphia, Pennsylvania, are required to submit to urine drug testing. During 11 months of 1996, a total of 1,469 urine samples were collected and tested for eight different drugs or classes of drugs of abuse. The urine samples collected during the first five months of 1996 were all analyzed using EMIT (Syva Corporation) and interpreted according to the guidelines established by the National Institutes of Drug Abuse (NIDA). Of 534 samples, 12 (2.2%) were reported as positive. During the last 6 months of 1996, a new methodology using a fluorescence polarization immunoassay (FPIA) was used. This assay had lower limits of quantification than EMIT, and more stringent interpretation guidelines than those of the NIDA were used. Of 935 samples analyzed by FPIA, 89 (9.5%) were positive. Of the 89 positive test results, 59 were below the cut-offs specified by the NIDA guidelines and would have been reported as negative. Interpretation of urine drug screen results according to the NIDA guidelines is not acceptable for clinical pharmacology investigations.

Selectivity of metoclopramide for endocrine versus renal effects of dopamine in normal humans.

The purpose of the present study was to evaluate the effect on renal function of dopamine (low dose, 2 micrograms/kg/min) inhibition by a low-dose infusion of metoclopramide. Prolactin and aldosterone levels were measured to assess metoclopramide's endocrine effects. Six salt-loaded subjects were studied by standard renal clearance techniques during water diuresis. Dopamine infusion produced an increase in renal plasma flow, fractional excretion of sodium, osmolar and free water clearances, urine volume, and solute delivery out of the proximal tubule. Solute and fluid absorption decreased in the distal nephron. These effects were evident within the first hour and peaked during the third hour. Metoclopramide slightly attenuated the dopamine-induced increase in renal plasma flow; statistical significance was obtained only during the second hour. None of the other renal function changes were inhibited. Serum prolactin and aldosterone levels were significantly increased following metoclopramide. Dopamine infusion attenuated the rise in prolactin levels but did not significantly affect aldosterone levels. The variance between previous reports and the present one may be due to the use of water diuresis, salt-loading, or methodological factors. Metoclopramide infused at 0.1 mg/kg/h appears selective for DA2 receptors, and low-dose dopamine-induced changes in renal function are DA1 receptor-mediated.