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The pharmacokinetics of diphenhydramine (DPHM) was compared in camels (n = 8) and horses (n = 6) following intravenous (i.v.) administration of a dose of 0.625 mg/kg body weight. In addition, the metabolism and urinary detection time of DPHM was evaluated in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows. The terminal elimination half lives (h) were 1.58 (1.13–2.58) and 6.11 (4.80–14.1), and the total body clearances (L/h per kg) were 1.42 (1.13–1.74) and 0.79 (0.66–0.90). The volumes of distribution at steady state (L/kg) were 2.38 (1.58–4.43) and 5.98 (4.60–8.31) and the volumes of the central compartment of the two compartment pharmacokinetic model were 1.58 (0.80–2.54) and 2.48 (1.79–3.17). All the pharmacokinetic parameters in camels were significantly different from those of horses. Five metabolites of DPHM were tentatively identified in the camel's urine. Two metabolites, diphenylmethoxyacetic acid and 1-(4-hydroxyphenyl)-phenylmethoxyacetic acid, were present in the acid fraction. Two metabolites, desamino-DPHM and diphenylmethanol, were identified in the basic fraction, in addition to DPHM itself, which was present mainly as a conjugate. Even after enzymatic hydrolysis, DPHM could be detected for up to 24 h in camels after an i.v. dose of 0.625 mg/kg body weight.