We have previously shown that a high-affinity monoclonal antibody fragment (Fab) against PCP is very effective in reversing PCP-induced behavioral effects and in rapidly redistributing PCP out of the CNS. The purpose of these studies was to optimize conditions for use of an antibody-based medication for PCP abuse, minimizing toxicity and maximizing therapeutic effectiveness. Although the Fab-PCP complex can be eliminated via the kidney, previous results showed only 21% of the anti-PCP Fab dose appears in the urine. The effect of fluid loading on anti-PCP Fab elimination was studied. Male Sprague- Dawley rats (n=4) received PCP (1 mg/kg i.v.) followed 10 min later by a mole equivalent anti-PCP Fab dose (1 mol-eq) with or without lactated ringer's (21 ml/kg i.v. over 9 min). Urine output was higher following fluid loading during the first 3 hr (P<.05), however anti- PCP Fab elimination did not differ between control and fluid loaded rats at any time point. The total amount of anti-PCP Fab appearing in the urine was 55.7 +/- 6.1% of the anti-PCP Fab dose compared to 64.1 +/- 10.3% of the dose without fluid loading. The effect of urinary alkalinization on PCP and anti-PCP Fab coelimination was also studied. Rats (n=4) received NaHCO3 at 8 min after PCP administration (8 mEq/kg + 2 mEq/kg every 45 min for 3 hr) followed 2 min later by anti-PCP Fab (1 mol-eq). Urinary alkalinization did not affect the cumulative amount of Fab being excreted (69.1 +/- 4.1%) or the co-elimination of PCP (41.4 +/- 7.2%). To study the effect of Fab dose on anti-PCP Fab elimination, rats (n=3-4) received PCP (0.1, 0.3, 1.0 and 3.0 mg/kg) followed 10 min later by a mol-eq Fab dose (21-617 mg/kg). Elimination of Fab following the 21 mg/kg dose (50.0 +/- 4.1%) was statistically lower than that of the 62 mg/kg (65.4 +/- 10.3%) and 617 mg/kg (66.0 +/- 6.7%) doses (P<.05), but not the 206 mg/kg dose (57.4 +/- 5.1%). Although urinary alkalinization did not alter the cumulative amount of Fab in the urine, it did appear to increase the rate at which it appeared, with urinary excretion being essentially complete within 2 hr. This is not consistent with reported serum pharmacokinetics of Fab which describe an initial distribution phase (t 1/2alpha = 0.2 - 2.4 hr) and a terminal elimination phase (t 1/2beta = 1.3 - 16.3 hr). These findings suggest the initial """"""""distribution phase"""""""" is actually a Fab renal elimination phase. This hypothesis is supported by PCKN studies in serum and urine. (This work is supported by NIDA grant DA07610, RSDA KO2 DA01 10 to S.M.O., and NRSA F3 1 DA05795 to J.W.P.).
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