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Plasma concentration-time profiles for amidopyrine and its primary desmethyl metabolite have been determined in control rats and in rats pretreated with phenobarbitone. The kinetics of both compounds indicate enhanced clearance following pretreatment. Metabolite excretion in urine, bile and breath support the plasma data. It would appear that phenobarbitone pretreatment results in quantitative but not qualitative changes in the metabolism of amidopyrine in rat.

The absorption of [14C] carbenoxolone from everted rat ileum in vitroand from rat stomach and ileum in situhas been examined. The rate of its mucosal to serosal transfer in vitroincreases as pH increases from 5 to 8 whereas the amount bound to ileum tissue decreases with increased pH; absorption closely parallels the drug's solubility. The uptake of carbenoxolone in situis bi-exponential and the rate constants for the two processes, have been calculated. Absorption in situ, and biliary excretion, of the drug increases with increasing pH from 5·0 to 7·4. Tissue binding to the ileum in situis not dependent on pH except below pH 5·0 when extensive tissue accumulation of carbenoxolone occurs because of its low solubility. Tissue binding to the stomach increases markedly with decrease of pH from 7·4 to 6·5 and at pH 6·5 is 80 times greater than binding to the intestine. The rate of absorption from the stomach, at pH 6·5–7·4, was much less than that from the intestine in situ. When allowance is made for the binding of carbenoxolone to the stomach, contrary to the pH-partition hypothesis, correlation is apparent between its absorption and the amount present in the ionized form.

The inhibition of prostaglandin E2(PGE2) synthesis by S-(+)-ibuprofen and piroxicam have been assessed following intravenous and regional (intrapouch) drug delivery using the rat air-pouch model of inflammation. Anti-inflammatory response was defined as the decrease in the area under the exudate PGE2concentration-time curve between 3 and 10 h, following regional administration of the irritant carrageenan.Dose-response studies indicated that bolus regional administration of S-(+)-ibuprofen increased potency 30-fold compared with systemic administration and could be further improved 10-fold by regional infusion, whereas regional administration of piroxicam showed no therapeutic advantage. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE2inflammatory response (3 to 10 h) was similar, irrespective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed for piroxicam, based on plasma concentration-response data, indicating a major systemic anti-inflammatory component for piroxicam but not for S-(+)-ibuprofen.These observations stress the need to take account of both pharmacodynamics and pharmacokinetics when considering the potential advantages of regional administration.

Promethazine blood concentration-time curves have been determined in 7 rabbits following intravenous, oral and hepatic portal vein administration of promethazine. This phenothiazine has a large volume of distribution and a high metabolic clearance resulting in low blood concentrations particularly when the oral route is used. Analysis of the areas under the blood concentration-time curves indicates that hepatic first-pass metabolism is the major determinant of promethazine’s low oral availability. Absorption from the gastrointestinal tract is essentially complete in most rabbits and the contribution of metabolism by the intestinal mucosa is minimal. The present findings are compared with the literature on other phenothiazines.

During a multiple dosing regimen, the area under the promethazine blood concentration-time profile progressively decreased indicating auto-induction of metabolism. The increase in promethazine clearance (mean 35%) was not reflected in changes in either elimination half-life or minimum blood concentrations during the dosing interval. This was attributed to a deep compartment in the disposition of promethazine in the rabbit. The changes in promethazine clearance were accompanied by proportionally larger changes in the clearance of the monodesmethylpromethazine metabolite. The effect of promethazine pretreatment on the clearance of antipyrine was also studied and was found to be significantly increased by a mean of 17% following pretreatment with promethazine. However, the changes in the clearance of antipyrine did not highly correlate with those of promethazine and monodesmethylpromethazine. This may indicate that promethazine induces metabolic systems in the rabbit for which antipyrine is not a good substrate.

The effect of cold stress and ether stress on mixed function oxidase activity in vivo has been studied using the aminopyrine-−14CO2exhalation rate (CER) method. Cold stress following both acute and chronic exposure resulted in enhanced rate of demethylation of both aminopyrine (CER α half-life) and its monomethyl metabolite (CER β half-life). However the time course of the response to cold stress differs for the two demethylations. The characteristics of the cold-induced enhancement of aminopyrine-CER would appear to differ in several aspects from that reported for phenobarbitone pretreatment. In contrast, ether exposure did not produce any consistent effect on drug metabolizing status of the rat.