Behavior of Chlorpheniramine in Vivo after Administration of d- and l-Chlorpheniramine Maleate

Fujiwara, Kazufumi; Iwamoto, Kenzo; Kawai, Sadao; Sakamoto, Teruo

doi:10.1248/yakushi1947.109.1_59

Cited by 11 publications

(8 citation statements)

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“…Studies in man have demonstrated higher serum levels and slower elimination of (+ )-chlorpheniramine following both simultaneous and separate administration of the isomers (Miyazaki & Abuki, 1976;Fujiwara et al, 1989). However, it is unlikely that such differences would explain entirely the differential effects of the isomers of chlorpheniramine observed in the present study in which higher doses were used.…”

Section: Discussioncontrasting

confidence: 50%

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Nicholson

Pascoe

Turner

et al. 1991

British J Pharmacology

118

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1 The effects of 10mg (+)-and (-)-chlorpheniramine and 5mg (+)-and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5mg triprolidine hydrochloride as an active control and two placebos. 2 Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+ )-chlorpheniramine. 3 Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4 In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine Hl-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

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Section: Discussioncontrasting

confidence: 50%

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Nicholson

Pascoe

Turner

et al. 1991

British J Pharmacology

118

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“…The fact that the level of DCPM formation did not depend on the route of administration indicates that very little or no monodesmethylation occurs during the in vivo absorption of CPAM in rats or that DCPM is further metabolized. Comparison of CPAM and DCPM AUCs after oral and IV administration shows that CPAM only undergoes a first-pass effect, which had been suggested in dogs by Fujiwara et al 9 The fact that a difference was observed between DCPM enantiomers after oral administration and not after IV administration suggests that this first-pass effect is stereoselective and that the intrinsic clearance of CPAM enantiomers is stereoselective. This phenomenon has been described for verapamil.…”

Section: Discussionmentioning

confidence: 52%

“…In humans, Miyazaki and Abuki, 6 Koch et al, 7 and Bui et al 8 reported higher plasma concentrations of the (+)-S-isomer when racemic CPAM was administered. In dogs, Fujiwara et al 9 also described stereoselectivity after oral administration of racemic CPAM, but not when injected IV, suggesting a stereoselective first-pass effect in the absorption process. Sakurai et al 10 reported higher plasma concentrations of the (−)-R-enantiomer after IV administration of the racemic mixture in the rat and concluded that this stereoselectivity could be due to differences in plasma protein binding.…”

mentioning

confidence: 99%

Intestinal absorption and metabolism of chlorpheniramine enantiomers in rat

et al. 2001

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Chlorpheniramine (CPAM) is a chiral antihistaminic drug commercialized as a racemic mixture. The intestinal absorption and metabolism of CPAM have been investigated in rat using in vivo (oral and IV administration), in situ (intestinal loop model), and in vitro (everted sac model) experiments. Oral and IV administrations of 20 mg/kg of the racemic mixture show that the pharmacokinetics of CPAM are stereoselective, with higher AUCs for the (+)-S-enantiomer compared to its antipode. The monodesmethyl metabolite (DCPM) was quantifiable in blood and its pharmacokinetics are stereoselective after oral but not after IV administration. Experiments using intestinal loops and everted sacs showed that the absorption is not stereoselective and that in vivo stereoselective formation of DCPM is presumably due to stereoselective hepatic metabolism. Moreover, the in vitro and in situ absorption of CPAM are not modified by modulators of P-glycoprotein and cytochromes P450 (cyclosporin A, ketoconazole).

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“…[2][3][4] In humans, daytime sleep latencies and performance on digit symbol substitution were reduced by (+)S-CPAM compared to its antipode. Fujiwara et al 8 also described stereoselectivity in the dog when CPAM was administered orally but not intravenously, suggesting a stereoselective first-pass effect. Koch et al 7 reported an approximately twofold higher AUC for the (+)S-enantiomer but similar half-lives for the two enantiomers.…”

mentioning

confidence: 99%

“…Koch et al 7 reported an approximately twofold higher AUC for the (+)S-enantiomer but similar half-lives for the two enantiomers. These four articles [6][7][8][9] have shown interspecies variation in stereoselectivity. Similarly, Sakurai et al 9 reported higher concentrations of the (−)R-enantiomer after IV administration of the racemic mixture in the rat.…”

mentioning

confidence: 99%

Stereospecific versus nonstereospecific assessments for the bioequivalence of two formulations of racemic chlorpheniramine

Hiep

Fernandez

Khanh³

et al. 2000

Chirality

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Chlorpheniramine (chlorphenamine, CPAM) is a racemic antihistaminic H1 drug containing two enantiomers. The aim of this study was to assess the bioequivalence of two formulations (reference and Vietnamese-tested formulation) of racemic chlorpheniramine combined with phenylpropanolamine in an open-labeled, randomized, crossover two-period study, after administration of 8 mg of racemic chlorpheniramine in 12 healthy Vietnamese subjects. First, dissolution of both formulations was tested in vitro according to USP requirements. Then the 12 subjects received both formulations after an overnight fast and a 7-day wash-out period. Plasma samples were collected up to 168 h. Plasma concentrations of total chlorpheniramine and its individual enantiomers were determined with a validated chiral HPLC method and pharmacokinetic parameters were estimated using model-independent analysis. For the reference formulation, Cmax and AUC values were higher for (+)S-chlorpheniramine ((+)S-CPAM) compared to (-)R-chlorpheniramine ((-)R-CPAM) (13.3 vs. 6.8 ng/ml and 409 vs. 222 ng/ml/h, respectively) while Clt/F and Vd/F were lower (9.8 vs. 17.6 l/h and 321 vs. 627 l, respectively). No difference was observed for Tmax, t(1/2), and MRT. Pharmacokinetic parameters were similar for the reference and the Vietnamese-tested formulation. Bioequivalence was assessed by Schuirmann test, as recommended by the current FDA and European Community criteria. Dissolution tests showed that both formulations were equivalent. A nonstereospecific, but not a stereospecific, approach indicated bioequivalence between the formulations.

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Behavior of Chlorpheniramine in Vivo after Administration of d- and l-Chlorpheniramine Maleate

Cited by 11 publications

References 0 publications

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Intestinal absorption and metabolism of chlorpheniramine enantiomers in rat

Stereospecific versus nonstereospecific assessments for the bioequivalence of two formulations of racemic chlorpheniramine

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Behavior of Chlorpheniramine in Vivo after Administration of d- and l-Chlorpheniramine Maleate

Cited by 11 publications

References 0 publications

Sedation and histamine H1‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H1‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Intestinal absorption and metabolism of chlorpheniramine enantiomers in rat

Stereospecific versus nonstereospecific assessments for the bioequivalence of two formulations of racemic chlorpheniramine

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Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene