Destruction of chlorpromazine during absorption in the rat <i>in vivo</i> and <i>in vitro</i>

Curry, Stephen H.; D'Mello, A; Mould, G P

doi:10.1111/j.1476-5381.1971.tb07125.x

Cited by 53 publications

(13 citation statements)

References 9 publications

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“…Following the observation that chlorpromazine was metabolised by an intestinal tissue preparation in vitro (Curry et al, 1971), the importance of gut wall metabolism of orally administered phenothiazines * Present address: Welsh School of Pharmacy, U.W.I.S.T., Cathays Park, Cardiff CF1 3NU 0306-5251/83/0300-0287 $02.00 has been widely accepted (Curry, 1976;Lader, 1976;Cooper, 1978;Davis et al, 1978). The evaluation of this hypothesis in man is difficult due to several technical and ethical problems.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man.

Taylor¹,

Jb²,

Shaffer³

et al. 1983

Brit J Clinical Pharma

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1 Blood concentrations of promethazine and promethazine sulphoxide have been measured following oral and intravenous administration of promethazine to seven healthy male volunteers. 2 Promethazine disposition is characterised by a large volume of distribution (1970 1) and a high blood clearance (1.141 min-'). Less than 1% of the dose is excreted unchanged in the urine, therefore total body clearance is essentially metabolic clearance. In accord with this high clearance the oral availability of promethazine is only 25%. The absorption of promethazine from the gastrointestinal tract exceeds 80% in most subjects. Minimal metabolism by the gastrointestinal mucosa is implicated. 3 Promethazine sulphoxide pharmacokinetics are consistent with a pronounced first pass effect. Although the area under the curve for this metabolite is not route dependent, there is a marked alteration in the shape of the metabolite curve when oral and intravenous data are compared. Evidence is presented to support the hypothesis that S-oxidation of promethazine is predominantly an hepatic event. The conclusions of previous investigators with regard to the role of the gut mucosa in S-oxidation of phenothiazines is critically assessed.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man.

Taylor¹,

Jb²,

Shaffer³

et al. 1983

Brit J Clinical Pharma

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“…However, with drugs like CPZ, which are highly and tightly bound to the gut walliS and metabolized in the gut, 4 slow gastric emptying can result in a decrease in both plasma peak levels and the area under the concentration-time curve. A study of the effect of lithium on gastric emptying in mans failed to demonstrate a consistent effect.…”

mentioning

confidence: 98%

Effect of lithium on plasma chlorpromazine levels

Rivera‐Calimlim

Kerzner

Karch

1978

Clin Pharma and Therapeutics

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The interaction of lithium and chlorpromazine (CPZ) was studied in healthy volunteers in a randomized crossover study. Each subject ingested two doses of CPZ (100 mg) as the liquid concentrate: (1) without concurrent lithium therapy and (2) after a 7-day treatment with lithium carbonate (900 mg/day). When CPZ was administered with lithium, peak plasma CPZ levels were 40.3% (mean) lower than those without lithium (p = 0.006), and the area under the CPZ plasma concentration time curve was 26.6% smaller (p = 0.08). The time to reach peak plasma CPZ levels was similar in both groups. All subjects slept for 4 to 6 hr after oral CPZ and had a maximum fall in both systolic (8 to 32 mg Hg) and diastolic (5 to 23 mg Hg) blood pressure at the time of peak plasma CPZ concentration. This lithium-CPZ interaction may explain the low plasma CPZ levels reported previously in psychiatric patients taking both lithium and CPZ.

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“…Hence, the low water solubility of ET by itself could explain the low oral bioavailability. In addition, presystemic metabolism by the gastrointestinal tract has been proposed to influence the bioavailability of another phenothiazine derivative, chlorpromazine [14]. Although it has been shown that intestinal metabolism of chlorpromazine can occur in vitro, the significance of this pathway towards reducing oral bioavailability has been the center of some attention.…”

Section: Resultsmentioning

confidence: 99%