Effects of aging and rifampicin pretreatment on the pharmacokinetics of human cytochrome P450 probes caffeine, warfarin, omeprazole, metoprolol and midazolam in common marmosets genotyped for cytochrome P450 2C19

Abstract

1. The pharmacokinetics were investigated for human cytochrome P450 probes after single intravenous and oral administrations of 0.20 and 1.0 mg/kg, respectively, of caffeine, warfarin, omeprazole, metoprolol and midazolam to aged (10-14 years old, n = 4) or rifampicin-treated/young (3 years old, n = 3) male common marmosets all genotyped as heterozygous for a cytochrome P450 2C19 variant. 2. Slopes of the plasma concentration-time curves after intravenous administration of warfarin and midazolam were slightly, but significantly (two-way analysis of variance), decreased in aged marmosets compared with young marmosets. The mean hepatic clearances determined by in silico fitting for individual pharmacokinetic models of warfarin and midazolam in the aged group were, respectively, 23% and 56% smaller than those for the young group. 3. Significantly enhanced plasma clearances of caffeine, warfarin, omeprazole and midazolam were evident in young marmosets pretreated with rifampicin (25 mg/kg daily for 4 days). Two- to three-fold increases in hepatic intrinsic clearance values were observed in the individual pharmacokinetic models. 4. The in vivo dispositions of multiple simultaneously administered drugs in old, young and P450-enzyme-induced marmosets were elucidated. The results suggest that common marmosets could be experimental models for aged, induced or polymorphic P450 enzymes in P450-dependent drug metabolism studies.

The use of midazolam as an appetite stimulant and anxiolytic in the common marmoset (Callithrix jacchus)

“…Although midazolam is well absorbed in the GI tract, its bioavailability is reported to be as low as 4% in marmosets due to extensive first-pass metabolism. 41,45,46 To mitigate these effects, we chose a dose that is two to five times higher than published parenteral doses in marmosets and is consistent with oral dosages published in human medicine. 40,42,46,47 Furthermore, to ensure our results were clinically applicable, we attempted to select the highest tolerable dose that did not cause overt sedation.…”

“…As few data exist on dosing of midazolam in marmosets, we sought to determine an optimal dose for our study, which was the highest dose that would not result in overt sedation or other adverse side effects. [40][41][42][43] We performed a dose determination trial in five, healthy, adult marmosets. These 5 animals were separate from the study group animals, but met the same inclusion criteria.…”

Current status of rivaroxaban in elderly patients with pulmonary embolism (Review)

“…In addition, since, heparin is a parenteral anticoagulant, its administration can be challenging for patients, as it must be injected subcutaneously, making it inconvenient and difficult to use at home. Warfarin, a vitamin K antagonist, exerts anticoagulant effects by inhibiting vitamin K, thereby subsequently activates clotting factors produced by the liver; however, as warfarin is primarily metabolized in the liver through the cytochrome P450 (CYP450) enzymes, the combination of warfarin and other drugs metabolized by the CYP450 pathways will affect the metabolism of warfarin (60). For example, certain cardiovascular drugs, such as amiodarone, digoxin and propranolol; antibiotics, such as rifampin, erythromycin, clarithromycin and metronidazole; antifungal drugs, such as fluconazole; and sedative drugs, such as barbiturates, have been demonstrated to increase or decrease the blood concentration of warfarin, which further affects its therapeutic effect (13).…”

Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model

“…The utility of physiologically based pharmacokinetic models was demonstrated in marmosets to help elucidate the inter-individual differences in the pharmacokinetics of R -omeprazole and S -warfarin associated with polymorphic P450 2C19 [14]. Moreover, the effects of aging or induction on some drug clearances mediated by marmoset P450 enzymes were evident in experiments on older animals and animals pretreated with rifampicin [15]. Additionally, marmoset P450 3A enzymes were strongly induced by exogenous rifampicin in vitro [16] and in vivo [15], just as human P450 3A enzymes are.…”

“…Moreover, the effects of aging or induction on some drug clearances mediated by marmoset P450 enzymes were evident in experiments on older animals and animals pretreated with rifampicin [15]. Additionally, marmoset P450 3A enzymes were strongly induced by exogenous rifampicin in vitro [16] and in vivo [15], just as human P450 3A enzymes are. Age-related pharmacokinetic changes in animal models could reveal important information during drug development for elderly patients.…”