On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquin

Medina, M.A.; Giachetti, Antonio; Shore, Parkhurst A.

doi:10.1016/0006-2952(69)90060-4

Cited by 71 publications

(19 citation statements)

References 19 publications

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“…MAO activity has been observed in microsomal preparations of rat liver (Gomez et al, 1988), and the present finding that phenelzine, an irreversible inhibitor of MAO, prevents the disappearance of DIP suggests that MAO activity is also associated with human liver microsomes. MAO-catalysed metabolism of DIP may explain the recent observation that the appearance of the end product of the side-chain oxidation of propranolol in humans is impaired by the coadministration of debrisoquine (Anthony et al, 1989), a known inhibitor of MAO activity (Medina et al, 1969).…”

Section: Discussionmentioning

confidence: 99%

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Otton

Lennard

et al. 1990

Brit J Clinical Pharma

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1 Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-4501ID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2 In the presence of NADPH and oxygen 4-and 5-hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N-desisopropylation. R(+)-propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N-desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N-desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3 Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4-and 5-hydroxylation occurred in microsomes from the EM livers only and b) side-chain oxidation was not observed under these conditions in either PM or EM livers. 4 Using cumene hydroperoxide to support the reactions, the 4-hydroxylation of propranolol showed little enantioselectivity, whereas S(-)-propranolol was 5-hydroxylated about twice as fast as the R(+)-enantiomer. There were highly significant correlations between the rates of 4-and 5-hydroxylation of R(+)-propranolol (r = 0.96, P < 0.001, n = 7 livers) and of S(-)-propranolol (r = 0.98, P < 0.001). Both oxidations were described by single-site Michaelis-Menten kinetics. 5 The findings suggest that P4501ID6 is involved in both the 4-and 5-hydroxylations of propranolol, but that these metabolites can also be formed by other P450 isoenzymes. It is confirmed that P450IID6 does not contribute to the N-desisopropylation of propranolol. Furthermore, the finding that mephenytoin did not inhibit the appearance of this metabolite is not consistent with the results of in vivo studies suggesting the involvement of the same enzyme in the side-chain oxidation of propranolol and the 4-hydroxylation of mephenytoin.

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Section: Discussionmentioning

confidence: 99%

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Otton

Lennard

et al. 1990

Brit J Clinical Pharma

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“…The distribution of debrisoquin following i.p. administration in rats is shown in Table 5 (MEDINA et al, 1969). Debrisoquin was concentrated in several organs, especially heart, as early as 30 min after injection.…”

Section: Ll Distribution Of Neuron Blocking Agents In Tissues Followingmentioning

confidence: 99%

Adrenergic Neuron Blocking Drugs

Maxwell¹,

Wastila²

1977

Antihypertensive Agents

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“…The transport system of human platelets has greater affinity for debrisoquin than for bretylium (25). After a single injection of debrisoquin to rats, the drug is found in the tissues upto 16 hr in concentrations that inhibit MAO (26). Debrisoquin is about 40 times more potent than bretylium in inhibiting rabbit liver MAO (26).…”

Section: Discussionmentioning

confidence: 99%

“…After a single injection of debrisoquin to rats, the drug is found in the tissues upto 16 hr in concentrations that inhibit MAO (26). Debrisoquin is about 40 times more potent than bretylium in inhibiting rabbit liver MAO (26). Further, debrisoquin inhibits human platelet MAO noncompetitively (13) and Furchgott et al (23) have shown with the guinea pig atria that bretylium inhibits the neu ronal MAO competitively.…”

Section: Discussionmentioning

confidence: 99%

Some Factors Affecting the Neuron Blocking Action of Guanethidine, Xylocholine, Bretylium and Debrisoquin

Prasad¹,

Shah²,

Gulati³

1973

Jpn.J.Pharmacol

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The uptake of guanethidine (3.3×10^-5 M), debrisoquin (8.4×10^-4 M), The uptake of noradrenaline (NA) by the adrenergic neuron is energy dependent (1, 2, 3) and sodium dependent (4,5,6, 7,8,9). Guanethidine utilises this NA uptake me chanism for transport across the membrane of neurons (10, 11) and of human platelets (12) which can serve as convenient model for the neuron (13). Support for this common transport mechanism for NA and guanethidine is derived from observations of the ability of NA to block the uptake of guanethidine, and the failure of uptake of guanethidine in sodium-deficient medium and under conditions of reduced energy supply as at low temp.(12). Gulati and Jaykar (14) showed that in the Finkleman preparation (15), the neuron blocking action of guanethidine was prevented by NA, sodium-deprivation and at low temp. and concluded that guanethidine shares the uptake mechanism for NA. Since the neuron blocking action of a neuron blocker is consequential upon the uptake by the neuron, the prevention of neuron block by various procedures and drugs affecting uptake of NA should provide information about the uptake of a neuron blocker. Thus the present cotn munication is concerned with the investigation of the influence of NA, low temp. and so dium-deprivation in modifying the adrenergic neuron blocking action on Hukovic pre paration (16) Of guanethidine, xylocholine, bretylitun and debrisoquin. In addition the mechanisms ol' the utitake Of these neuron bloekers into the adrenergic neurons are dis cussed.

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On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquin

Cited by 71 publications

References 19 publications

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Adrenergic Neuron Blocking Drugs

Some Factors Affecting the Neuron Blocking Action of Guanethidine, Xylocholine, Bretylium and Debrisoquin

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