The Metabolic Fate of Tolbutamide in Man and in the Rat

Thomas, Richard; Ikeda, George J.

doi:10.1021/jm00322a014

Cited by 134 publications

(58 citation statements)

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“…The major excretory metabolite in human and rat is 4-hydroxytolbutamide (5a) catalyzed mainly by CYP2C9, with some production of 4-carboxytolbutamide (5b) as well (Thomas and Ikeda, 1966). In our study with multispecies MPCC hepatocytes, human donors were able to produce 4-hydroxy tolbutamide (5a) as the major metabolite with smaller amounts of carboxytolbutamide (5b) formed.…”

Section: Resultsmentioning

confidence: 63%

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Ballard

Wang

Cox

et al. 2016

Drug Metabolism and Disposition

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Laboratory animal models are the industry standard for preclinical risk assessment of drug candidates. Thus, it is important that these species possess profiles of drug metabolites that are similar to those anticipated in human, since metabolites also could be responsible for biologic activities or unanticipated toxicity. Under most circumstances, preclinical species reflect human in vivo metabolites well; however, there have been several notable exceptions, and understanding and predicting these exceptions with an in vitro system would be very useful. Human micropatterned cocultured (MPCC) hepatocytes have been shown to recapitulate human in vivo qualitative metabolic profiles, but the same demonstration has not been performed yet for laboratory animal species. In this study, we investigated several compounds that are known to produce human-unique metabolites through CYP2C9, UGT1A4, aldehyde oxidase (AO), or N-acetyltransferase that were poorly covered or not detected at all in the selected preclinical species. To perform our investigation we used 24-well MPCC hepatocyte plates having three individual human donors and a single donor each of monkey, dog, and rat to study drug metabolism at four time points per species. Through the use of the multispecies MPCC hepatocyte system, the metabolite profiles of the selected compounds in human donors effectively captured the qualitative in vivo metabolite profile with respect to the human metabolite of interest. Human-unique metabolites that were not detected in vivo in certain preclinical species (normally dog and rat) were also not generated in the corresponding species in vitro, confirming that the MPCC hepatocytes can provide an assessment of preclinical species metabolism. From these results, we conclude that multispecies MPCC hepatocyte plates could be used as an effective in vitro tool for preclinical understanding of species metabolism relative to humans and aid in the choice of appropriate preclinical models.

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Section: Resultsmentioning

confidence: 63%

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Ballard

Wang

Cox

et al. 2016

Drug Metabolism and Disposition

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“…The calculated probability of demonstrating a 20% change in lignocaine CL by either atenolol or metoprolol was > 0.99 at the 5% level and > 0.90 at the 1% level; likewise, for a 30% change in lignocaine CL0 the calculated (Nelson & O'Reilly, 1961;Thomas & Ikeda, 1966). Since tolbutamide clearance is limited by hepatic metabolic capacity ('low clearance' drug), the lack of effect of any of the ,B-adrenoceptor blockers on tolbutamide systemic clearance indicates that these agents do not inhibit the enzyme(s) responsible for tolbutamide metabolism.…”

Section: Resultsmentioning

confidence: 96%

Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

Miners¹,

Wing²,

Lillywhite³

et al. 1984

Brit J Clinical Pharma

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The effects of separate 1 week pre‐treatments with each of the beta‐ adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre‐treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half‐life, volume of distribution and plasma protein binding were not altered by the beta‐ adrenoceptor blocker pre‐treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. ‘Therapeutic’ plasma concentrations of the beta‐adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta‐ adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration‐dependent.

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“…As the rate-limiting step for tolbutamide clearance is oxidation to hydroxytolbutamide (Thomas & Ikeda, 1966) (Dubach et al, 1966;Hansen et al, 1979;O'Reilly, 1980 (Patel & Welling, 1980) and thus the active amounts of each drug in the body will not necessarily be present in predictable proportions. It should be pointed out that the metabolic inhibitory effects of sulphamethoxazole and trimethoprim may be quantitatively different for different forms of cytochrome P-450.…”

Section: Discussionmentioning

confidence: 99%

Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

Wing

Miners

1985

Brit J Clinical Pharma

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The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions-as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P < 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P < 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (Vss) was increased by 10% in the S and ST phases (P < 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound Vss following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.

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The Metabolic Fate of Tolbutamide in Man and in the Rat

Cited by 134 publications

References 1 publication

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

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