Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism*

Thummel, Kenneth E.; O’Shea, Diarmuid; Paine, Mary F.; Shen, Danny D.; Kunze, Kent L.; Perkins, James D.; Wilkinson, Grant R.

doi:10.1016/s0009-9236(96)90177-0

Cited by 542 publications

(482 citation statements)

References 25 publications

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“…The BA of midazolam in humans was previously reported to be 30.0% [61]. The BA of midazolam in microminipigs was similar to that in humans, while the CL int values in the other animals were within approximately ± 3-fold that in humans.…”

Section: Discussionsupporting

confidence: 66%

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

S¹

2015

J Drug Metab Toxicol

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To clarify species differences in the pharmacokinetic parameters of cytochrome P450 (CYP) activities between humans and experimental animals, we assessed several CYP activities in mice, rats, dogs, monkeys, and microminipigs, using the simultaneous administration of typical human CYP substrates, such as caffeine (human CYP1A2 substrate), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A), to these animals. The intrinsic clearance (CL int ) of these 5 substrates was also examined using the liver microsomes of humans and the experimental animals. The high bioavailabilities (BAs) and low CL int values of caffeine in the experimental animals were similar to those in humans. Mice and monkeys had lower BAs and higher CL int values of losartan than those in humans. Mice, rats, and monkeys had lower BAs and higher CL int values of omeprazole than those in humans. The lowest BAs of dextromethorphan were observed in monkeys and microminipigs, and only the CL int in dogs was similar to that in humans. The BA of midazolam in microminipigs only was similar to that in humans, while the CL int values in the other animals were similar to that in humans. These results indicated that in vitro and in vivo experimental data obtained using multiple animals including microminipigs are useful for predicting human pharmacokinetics.

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Section: Discussionsupporting

confidence: 66%

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

S¹

2015

J Drug Metab Toxicol

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“…Since C max and AUC are direct indicators of the extent of absorption, the observed increases in these parameters supports the idea that in birds that died, zero-order metabolism was occurring. Similar increases in AUC and C max have been described for midazolam in humans, and this was reportedly linked to saturation of the presystemic elimination pathways (Bornemann et al 1985;Thummel et al 1996).…”

Section: Discussionsupporting

confidence: 70%

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Naidoo

Venter

Wolter³

et al. 2010

Arch Toxicol

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In a safety study, Cape GriVon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of »1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUC inf , V z and Cl being 10.42 g/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUC inf , V z and Cl in the birds that survived were 52.26 g/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUC inf , V z and Cl in the birds those died were 207.90 g/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUC inf and C max in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic diVerences in the cytochrome P450 pathway.

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“…The interindividual variability contributes to the variability in blood levels of orally administered drugs that are substrates of CYP3A4. [13][14][15][16] Mucosal CYP3A4 activity can be inhibited by grapefruit juice and occurs probably instantaneously. In a human volunteer, mucosal CYP3A4 activity estimated in mucosal biopsies taken 4 hr after grapefruit juice was administered decreased 47%.…”

Section: Discussionmentioning

confidence: 99%

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

Nagy¹,

Schipper²,

Koopmans³

et al. 2002

Am J Trop Med Hyg

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Abstract. The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (C max ) was enhanced 6.5-fold by a fatty meal (from 0.24 ± 0.09 mg/l to 1.55 ± 0.30 mg/l; mean ± SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 ± 0.09 mg/l to 0.76 ± 0.37 mg/L; P ‫ס‬ 0.031). When grapefruit juice was combined with cimetidine, C max was significantly lower than with grapefruit juice alone (0.41 ± 0.29 mg/l and 0.76 ± 0.37 mg/l, respectively; P ‫ס‬ 0.022). The area under the concentration-time curve from 0 to infinity (AUC 0-⍀ ) followed a comparable pattern. Half-life (T 1/2 ) was 8.8 ± 4.2 hr and 8.2 ± 4.3 hr after administration with water or a fatty meal (P ‫ס‬ 1.000). Grapefruit juice shortened T 1/2 by 46% (P ‫ס‬ 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.

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Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism*

Cited by 542 publications

References 25 publications

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

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