Overview of PCP and Sample Handling

Phencyclidine is formally named 1-{1-phenylcyclohexyl)piperidine with the empirical formula C17H25N and a molecular weight of 243.38. In its pure form it is a colorless-to-white crystalline solid with a melting point of 46-46.5 °C and a boiling point of 135-137 °C at 1 mmHg. It is a weak organic base with a PKa of 8.5 and is soluble in most common organic solvents and in aqueous acid. The acidic solution exhibits absolutions in the ultraviolet UV spectrum at 252, 258, 263, and 270 nm. The mass spectrum has principal peaks at m/z 200 (base peak), 91, 243 Molecular ion), 242, 84, 186, and 166.

The hydrochloride salt is a white crystalline solid, Mr = 279.83, with a melting point of 233-235 °C. The hydrobromide salt, Mr – 324.28, has also been reported as a solid with a melting point of 214-218 °C. Both salts are soluble in water and ethanol, slightly soluble in chloroform, and almost insoluble in ether.

Caution should be exercised when handling PCP, it salts, or analogs, because trans-dermal absorption of the drug is possible. Inadvertent trans-dermal absorption from contaminated clothing has been reported. PCP can also be absorbed by oral or nasal routes during handling of the drug. Phencyclidine is a remarkably stable compound in biological samples. Phencyclidine concentrations remain almost unchanged for up to 5 years in samples of blood preserved with sodium fluoride and potassium oxalate and stored at room temperature. Refrigeration at 4 °C is sufficient for short-term storage of urine specimens. Frozen storage at -20 °C will preserve PCP in urine specimens for at least 12 months. Storage of urine specimens as dried stains on filter paper has proved to be a feasible technique.

Liberation, Absorption, Disposition, Metabolism, Elimination

Ppremature clinical trials of Phencyclidine used intravenous and oral routes of administration. Since the advent of PCP as a common drug of abuse, many studies have explored the routes of administration more commonly seen illicit PCP use. Phencyclidine can be ingested by all of the usual routes of administration including inhalation, insufflation, intravenous erection of aqueous solutions and trans-dermal absorption, as well as oral, rectal, and vaginal absorption. One of the most common methods used for PCP ingestion is to apply the drug to standard cigarettes and inhale the smoke. Phencyclidine can also be placed on other vegetable materials, which are then smoked, including parsley, oregano, mint, tea leaves, or marijuana. Oral ingestion of 3 to 8 mg produces lethargy, disorientation, hallucinations, and loss of coordination. Increasing the dosage to 7.5 mg produces staggering gait and slowed reaction times, while anesthesia and coma occur at an oral dose of 20 mg. Inhalation of 1 to 2 mg produces nystagmus and a self-reported “high” feeling, which users describe as being similar to marijuana (40). As the inhaled dosage is increased, memory impairment and ataxia appear at doses of 7 mg, marked analgesia at 8-9 mg, and prostration and collapse at 15 mg. The IV administration of 0.8 to 1.0 mg produces a self-reported high proceeding to complete anesthesia at 15 mg. Very high doses (>50 mg) can produce seizures.

Characteristic street doses contain approximately 3 to 5 mg of PCP, usually as the hydrochloride salt. Leafy mixtures typically contain about 1 mg of PVP per 150 mg of plant material, but may range from 0.25 to 8.0% PCP. A typical cigarette may contain 5 to 50 mg or more of PCP. The preparation of illicit PCP dosage units is a rather inexact science and the concentrations seen in street drugs vary considerably. Analyses of street preparations have produced results varying from 7 to 99%. According to the US Department of Justice, the street price of PCP varies from $125 to $600/oz for the powder or liquid, and $5 to $30 for a full length cigarette saturated with PCP.

Controlled studies after the administration of large psychoactive doses have not been performed because of concern about the unpredictable side effects of the drug. Considerable data are available from individuals arrested for being under the influence of the drug, and pharmacological data can be inferred from these data.

Serum concentrations of PCP do not correlate well with observed behavior. Blood concentrations of PCP in 26 subjects arrested for public intoxication or driving under the influence (DUI) ranged from 7 to 240 ng/mL, averaging 75ng/mL. In another study, 65 persons arrested for DUI had blood levels ranging from 12 to 118ng/mL. Other studies of subjects who were in the early stages of PCP intoxication showed serum concentrations ranging from 0 to 800ng/mL, while patients in a coma induced by a PCP overdose have had serum levels of 50 to 3,700 ng/mL. As with most drugs, urine concentrations of PCP have no relationship to behavior. In one study of 19 impaired patients, Moe urine concentrations ranged from 400 to 340,000 g/mL. Chronic phencyclidine users who have stopped using the drug for a period of time can exhibit detectable urine levels of PCP for as long as 5 weeks after their last reported use. This is most likely due to the release of PCP from body stores in adipose tissue.

In 10 deaths associated with asphyxia by drowning or trauma PCP blood concentrations ranged from 100 to 1,200 ng/mI mean of 600ng/mL. Urine levels in 5 of these cases ranged from 500 to 10,600 ng/^TnL. In 6 cases in which the cause of death was unknown, blood PCP concentrations ranged from 3,000 to 6,000ng/mL (mean of 2,900ng/mL). Urine levels ranged from 5,100 to 33,000 ng/ mL. In 17 cases in which the cause of death was determined to be accidental or intentional ingestion of PCP, serum levels ranged from 300 to 25,000 ng/mL (mean 4,800 ng/mL).

Phencyclidine is also absorbed by other routes of administration. Intravenous administration results in a very rapid (seconds) onset of action, with peak effects reached after 10 min. Interestingly, studies with IV administration of a single bolus of PCP in rats have shown that the peak PCP concentration in the brain occurs at 30 s. This apparent contradiction with the onset of peak effects is probably due to the fact that the serum level decreases 30 times faster than the brain concentration. Thus, the drug reaches a peak at 30 s, but tends to remain in the brain for a longer period of time than the blood levels would indicate.

When the drug is applied to plant material and smoked, effects are felt within 1 min (peak at 30 min). Insulation (“snorting” the PCP hydrochloride salt) results in effects within several minutes. When taken orally as capsules containing the hydrochloride, initial effects are felt after 20 to 40 min. with peak effects after 90 min. When taken as a street drug, the thighs lasts 4 to 8 h, with subjective effects possibly being felt for 24 to 48 h. Flashbacks have been reported months or years after the last ingestion, but because of the spontaneous occurrence of these episodes, verification has been difficult.

Tritium-labeled PCP hydrochloride was administered to normal volunteers in an elimination study. About 75% of the total dose was recovered in urine over 10 days, with 50% of that being recovered in the first 2 days. Approximately 5% was recovered in the feces and very small but detectable amounts were excreted in sweat and saliva. Between 4 and 19% of the administered dose is recovered as unchanged PCP in the urine. The remainder is polar metabolites, chiefly resulting from hydroxylation on the cyclohexane ring (20%), piperidine ring (8%), or both (3%). About 85% of the hydroxylated metabolites are glucuronide or sulfate conjugates. Further metabolism of the 4-hydroxylated piperidine metabolite results in a ring opened product, 5-(1-phenylcyclohexylamino}valeric acid (Figure 11-1). This ring-opened metabolite seems to be the major metabolite deposited in meconium when PCP is used during pregnancy. Other metabolites exist but remain unidentified.

Early reports suggested that none of the PCP metabolizes was behaviorally active. More recent studies have suggested otherwise. The major metabolite of PCP is the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol (4-PPC). Studies have shown that this major metabolite may contribute to the psychotomimetic effects of PCP.

The availability of PCP from smoking appears to be appropriately 40%, with close to 31% of the original PCP pyrolyzed to 1-phenyl-1cyclohexene (PC) by the heat of the burning cigarette. Animal studies have shown that PC itself is further metabolized to 3-phenylcyclohexen-1-ol and 3-phenylcyclohex-2-en-1-one. PC itself has not been shown to possess significant biological activity.

When ingested, PCP is rapidly transported from the blood into brain and adipose tissue with a distribution half-life of 1 to 4 h and a plasma clearance of 0.25-0.30 L/kg/h. The plasma elimination half-life varies depending on dosage. In overdose patients the elimination half-life ranges from 11 to 89 h, while in volunteers given low doses of the drug, half-life is in the range of 7 to 50 h (mean 17.6 h). Frequent users exhibit a 2-compartment elimination mechanism where PCP is slowly released from tissue compartments over a long period of time. The existence of a large tissue store of the drug is supported by a large apparent volume of distribution (5.4-7.5 L/kg/hr). In rats, the brain/plasma PCP ratio is about 7:1 after a single dose, and the fat/plasma ratio can be as high as 100:1.

Removal of PCP through the kidneys can be significantly enhanced by acidification of the urine. With a urine pH of 6.5, about 90% of PCP clearance is through metabolic processes. Acidification of the urine to a pH of 4 results in significant increases in the amount of unchanged drug passing directly into the urine, thereby increasing the rate of renal clearance. Renal clearance of PCP depends on both urinary pH and urinary output. Acidification of urine to pH 6.0 (from the usual 6.5) increases renal clearance about 5-fold (from 30 to 135 mL/min) and the urine/plasma PCP ratio about 10-fold. The addition of forced diuresis to increase urinary output increases renal clearance about 10-fold (to 300 mL/min).

Target Analytes

The analysis of workplace specimens for phencyclidine in most laboratories is focused on the detection of the parent drug, PCP. The major metabolites of PCP are 4-Phenyl-4-piperidinylcyclohexanol, accounting for about 20%of the metabolites, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine. About 8% of the metabolites), both appearing in the urine as glucuronide and sulfate conjugates.

Although the method for the hydrolysis of glucuronide metabolites is well established and widely used in cannabinoid, anabolic steroid and opiate analysis, this procedure has not been incorporated into PCP analysis. Perhaps this is because most immunoassay-positive specimens confirm by gas chromatography-mass spectrometry (GC-MS). Drug metabolite identification is touted as a major criterion for distinguishing external contamination from drug ingestion, both in urine and in hair.

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