A Comparison of the Effects of Imipramine, Trimipramine, and Some Other Drugs in Rabbits Treated With a Monoamine Oxidase Inhibitor

Summary1. N-Demethylation of pethidine was studied in microsomal suspensions from unstarved male rat liver and the N-demethylase identified as belonging to the class of hepatic microsomal mixed function oxidases. 2. A study of the structure/action relationships of compounds inhibiting pethidine N-demethylase revealed that hydrazine derivatives including phenylhydrazine, methylphenylhydrazine and mebanazine were all potent competitive inhibitors.3. Pethidine N-demethylase was only slightly inhibited by histamine and amphetamine but not by adrenaline and ephedrine nor by several miscellaneous compounds including piperidine, N-ethylpiperidine, N-methylpiperidine, Nmethylammonium, hydrallazine or pethidinic acid. 4. Several psychotropic drugs were all found to be potent competitive inhibitors of pethidine N-demethylase. 5. These results are discussed in relation to the clinically observed drug interactions which may occur between monoamineoxidase inhibitors and pethidine. It is concluded that since many different groups of drugs, including monoamineoxidase inhibitors, tranquillizers, tricyclic antidepressants, steroids, nalorphine, SKF 525A and barbiturates compete for cytochrome P450 reductase, it is possible that this mechanism may account, at least in part, for the observed interactions of these various drugs in man.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of the inhibition of pethidine N‐demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man

Clark¹,

Thompson²,

Widdrington³

1972

“…However, there is evidence that 5-HT, noradrenaline and dopamine modify the analgesic action of morphine and related drugs (Saarnivaara, 1969a, b;Takagi & Nakama, 1968;Tenen, 1968). Moreover, the inhibitory effect of analgesics on monamine uptake could at least partially explain the toxic reactions seen when analgesics are combined with drugs which increase the monoamine concentration at synapses (Loveless & Maxwell, 1965;Mustala & Jounela, 1966). Therefore, although the inhibitory effects of narcotic analgesics on monoamine uptake by platelets do not correlate with their pain-relieving properties, the.…”

Section: Discussionmentioning

confidence: 99%

The effect of narcotic analgesics on the uptake of 5‐hydroxytryptamine and (—)‐metaraminol by blood platelets

Ahtee

Saarnivaara

1973

Summary1. The effects of narcotic analgesic and related drugs were studied on the uptake of 5-hydroxytryptamine (5-HT) and (-)-metaraminol by blood platelets.2. The most potent drug in inhibiting the uptake of 5-HT (10 FLM) by human platelets was methadone, followed by pentazocine>piminodine-pethidineanileridine cyclazocine thebaine > dextropropoxyphene. Alphaprodine, papaverine, apomorphine, nalorphine, codeine, and morphine were almost without effect. Methadone was slightly less active than desipramine, and had 10% of the activity of imipramine under similar conditions. Naloxone did not antagonize the effect of methadone on 5-HT uptake.3. The most potent inhibitor of metaraminol (3 jM) uptake by human platelets was piminodine, followed by pentazocineRanileridine>cyclazocine= methadone > dextropropoxyphene -thebaine > papaverine -alphaprodine >pethidine>morphine. The activity of morphine was 1% of that of piminodine. Piminodine was more potent than desipramine and protriptyline under similar conditions. The order of potency of drugs studied in inhibiting the uptake of metaraminol by rabbit platelets was similar to that obtained with human platelets. 4. The effects of the analgesics studied on inhibiting uptake of monoamines did not correlate with their pain-relieving properties. IntroductionThe uptake and storage of 5-hydroxytryptamine (5-HT) by blood platelets closely resembles that which occurs in neurones. Moreover, the inhibition of this uptake by drugs is similar to that found in neurones (Paasonen, 1968;Paasonen, Ahtee & Solatunturi, 1971;Stacey, 1961; Todrick & Tait, 1969). We have recently shown that the orders of potency of tricyclic anti-depressants in inhibiting the uptake of 5-HT and a noradrenaline analogue, metaraminol, by human blood platelets were different. These drugs had a similar order of activity in inhibiting the uptake of 5-HT by platelets and in preventing the uptake of 5-HT by neurones, whereas their effects on the uptake of metaraminol by platelets paralleled their potencies in blocking the uptake of noradrenaline into neurones (Ahtee & Saarnivaara, 1971b).The present work was undertaken to find out if narcotic analgesics inhibit the uptake of 5-HT and metaraminol by platelets because there is evidence that several

“…All of these agents exhibit a characteristic interaction with MAO inhibitors in rabbits (Nymark & Nielsen, 1963;Loveless & Maxwell, 1965;Penn & Rogers, 1971;Fahim et al, 1972;Sinclair, 1972Sinclair, , 1973.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that pethidine causes excitation and hyperpyrexia in rabbits pretreated with MAO inhibitors (Nymark & Nielsen, 1963;Loveless & Maxwell, 1965;Penn & Rogers, 1971;Fahim, Ismail & Osman, 1972;Sinclair, 1972 24 and 12 h before pethidine; oxytetracycine (50 mg/kg i.p.) twice daily and also once daily orally (50 mg/kg) for seven days before pethidine; DDT (50 mg/kg i.p.)…”

Section: Introductionmentioning

confidence: 99%

Furazolidone‐pethidine Interaction in Rabbits

Eltayeb

Osman

1975

I The intravenous injection of pethidine in rabbits pretreated with furazolidone administered orally but not systemically resulted in severe interaction and fatal hyperpyrexia. 2 Treatment with p-chlorophenylalanine, chloropromazine or cyproheptadine protected the rabbits against the furazolidone-pethidine interaction, while a-methyl-p-tyrosine was ineffective. 3 5-Hydroxytryptophan produced a fatal hyperpyrexia in furazolidone pretreated rabbits. 4 Pretreatment of rabbits with 1,1 ,1-trichloro-2, 2-bis(p-chlorophenyl)ethane (DDT) accelerated and enhanced the furazolidone-pethidine interaction, while oxytetracycline pretreatment completely prevented the interaction. 5 It is concluded that furazolidone-pethidine interaction might depend mainly on potentiation of the effects of 5-hydroxytryptamine in the CNS and that the transformation of furazolidone into an active monoamine oxidase inhibitor metabolite might occur mainly in the gut microflora in the gut lumen.