PHARMACOKINETICS AND KINETIC-DYNAMIC MODELING OF AMINOPHENONES AS METHEMOGLOBIN FORMERS

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a v ariety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis fo r the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemogl obin levels for two candidate anti-cyanide compounds. The compounds st udied were the aminophenones p-aminopropiophenone (PAPP) and p-aminohe ptylphenone (PAHP). Both PAPP and PAHP were given as intravenous bolus es and as two different oral formulations. The kinetics of both compou nds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral adminis tration. The first distribution phase seen with the intravenous admini stration was obscured by the absorption phase during oral administrati on. Bioavailability for all formulations varied between 20 and 47%. Fo r both compounds there was a delay between the appearance of drug in t he plasma and the appearance of methaemoglobin (counter-clockwise hyst eresis) which is suggestive of an active metabolite causing methaemogl obin formation. The pharmacodynamics were fit with an effect-compartme nt kinetic-dynamic model linked to a sigmoid E(max) pharmacodynamic mo del. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously e stimates of EC50 were lower than the estimates of EC50 from oral admin istration for both compounds. This might be because of oral first-pass inactivation or a 'first-pass' activation through the lungs contribut ing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near base line within 12 h. Both compounds seem to produce sufficient methaemogl obin to treat acute cyanide poisoning and to serve as prophylactic age nts against acute cyanide poisoning in a military setting.