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Phenazepam

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Occurrence and Usage. Phenazepam (fenazepam) is a benzodiazepine derivative, structurally similar to

bromazepam and lorazepam, that has been used clinically since 1978 as a sedative-hypnotic drug, principally

in Russia. It is supplied as the free base in 0.5–2 mg tablets for oral administration. Adult doses are normally

0.5 mg 2–3 times daily for treatment of anxiety.

Blood Concentrations. Two healthy volunteers given unusually large single oral 3 or 5 mg doses attained peak whole blood phenazepam concentrations averaging 24 or 38 µg/L, respectively, at 4 hours and declining with an average elimination half-life of 60 hours; blood levels of 3-OH-prazepam, if present, were less than 3 µg/L (Zherdev et al., 1982).

Metabolism and Excretion. A single labeled intraperitoneal dose of phenazepam administered to rats was eliminated to the extent of 77% in urine and feces over a 5 day period. A pharmacologically active metabolite, 3-OH-phenazepam, has been found to accumulate in plasma of experimental animals but not in man (Zinkovskii

et al., 1979; Golovenko et al., 1980; Zherdev et al., 1982).

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Toxicity. The adverse effects of phenazepam therapy can include somnolence, dizziness, incoordination and asthenia. Pediatric victims of acute poisoning, ages 11–14 years, exhibited somnolence and an average blood

phenazepam level of 2.5 µg/L, ataxia at 2.7 µg/L and drug-induced sleep at 3.3 µg/L (Luzhnikov et al., 2010).

A

group of 20 persons arrested for impaired driving had blood phenazepam levels of 18–400 µg/L (Mykkanen

et

al., 2004). In 4 other driving arrests, blood phenazepam levels of 280–550 µg/L were measured (Johnson et

al., 2010). A 42 year old man was found dead following acute oral ingestion of phenazepam and poppy seed tea; post- mortem blood contained unconjugated phenazepam, morphine and codeine at concentrations of 386, 116 and 85 µgL, respectively (Bailey et al., 2010).

Analysis. Phenazepam has been quantitated in biofluids by gas chromatography with electron-capture (Ekono- mov and Zherdev, 1980) or mass spectrometric detection (Gunnar et al., 2005). Liquid chromatography-mass spectrometry has also been applied (Bailey et al., 2010).

References

K. Bailey, L. Richards-Waugh, D. Clay et al. Fatality involving the ingestion of phenazepam and poppy seed tea. J. Anal. Tox. 34: 527–532, 2010.

A.L. Ekonomov and V.P. Zherdev. Method of quantitative gas-chromatographic determination of phenazepam and its metabolite 3-hydroxy-

phenazepam in plasma. Pharmaceut. Chem. J. 14: 579–582, 1980.

N.

Golovenko, V.G. Zinkovskii, S.B. Seredenin et al. Distribution of 14 C-phenazepam and its metabolites in the liver, brain and blood plasma

in single and prolonged administration to white rats. Farm. Tok. 43: 144–148, 1980.

T.

Gunnar, K. Ariniemi and P. Lillsunde. Determination of 14 benzodiazepines and hydroxy metabolites, zaleplon and zolpidem as tert - butyldimethylsilyl derivatives compared with other common silylating reagents in whole blood by gas chromatography-mass spectrometry. J. Chrom. B 818: 175–189, 2005.

W.

Johnson. Phenazepam in Wisconsin drivers. Presented at the annual meeting of the Society of Forensic Toxicologists, Richmond, Virginia,

October 20, 2010. E.A. Luzhnikov, G.N. Sukhodolova, Y.N. Ostapenko et al. Clinical toxicometry of acute poisonings by fenazepam in older children. Clin. Tox. 48: 282, 2010.

S. Mykkanen, T. Gunnar, K. Ariniemi et al. Quantitation of phenazepam in blood by GC-MS in positive drug-driving cases in Finland. Presented

at the annual meeting of the Society of Forensic Toxicologists, Washington DC, September 1, 2004. V.P. Zherdev, S. Caccia, S. Garattini and A.L. Ekonomov. Species differences in phenazepam kinetics and metabolism. Eur. J. Drug Metab. Pharm. 7: 191–196, 1982. V.G. Zinkovskii, A.V. Bogatskii, N.I. Golovenko et al. Kinetics of phenazepam- 14 C excretion from the body of white rats in the single and prolonged administration of the preparation. Biull. Eksp. Biol. Med. 87: 561–563, 1979.