Age-related changes of hepatic clearances of cytochrome P450 probes, midazolam andR-/S-warfarin in combination with caffeine, omeprazole and metoprolol in cynomolgus monkeys usingin vitro–in vivocorrelation

Abstract

1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) were investigated after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, in combination to three young (3-year-old) and three aged (16-year-old) cynomolgus monkeys. 2. The plasma concentrations of caffeine and R-/S-warfarin decreased slowly in a monophasic manner, but those of omeprazole, metoprolol and midazolam decreased rapidly, in a similar manner to those as reported for pharmacokinetics in humans. 3. The mean maximum concentrations of R- and S-warfarin (4.6 and 3.7 µg/mL, respectively) in aged monkeys after oral administration were significantly higher than those in young monkeys (3.3 and 2.7 µg/mL). The mean clearance (CL) values of midazolam in aged monkeys (9.5 mL/min/kg) were significantly lower than those in young monkeys (13 mL/min/kg). 4. Individual intrinsic CL values for omeprazole (r = 0.29) and metoprolol (r = 0.30) of individual monkey livers were inversely correlated with their ages significantly (p < 0.05) in liver microsomes prepared from 55 cynomolgus monkeys. 5. These results suggest that cynomolgus monkeys could be a good model for humans, especially with particular characteristics in reduced CLs of some human P450 substrates by aging.

Utility of non-human primates in drug development: Comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes

“…During drug development, it is important to predict how the pharmacokinetics of drug candidates will change in older patients to reduce related risks. Cynomolgus monkeys (aged 16 years) may be a suitable animal model to predict the age-related alterations of pharmacokinetics and physiological parameters in humans, because age-related alterations of physiological parameters or reduced hepatic clearances of some human P450 substrates in cynomolgus monkeys are in agreement with clinical observations in humans [18,37], as briefly indicated in Table 4. At least, cynomolgus monkey P450 2C19-and P450 3A-mediated drug clearances showed similar age-related decreases in hepatic clearance values to those of humans (Table 4).…”

“…In vivo caffeine elimination rates in plasma were similar among marmosets, cynomolgus monkeys, and humans [18,19]; however, main caffeine metabolite formations were 7-N-demethylation (theophylline formation) in cynomolgus monkeys [29] and [30] in marmosets (Fig. 1), mainly mediated by cynomolgus monkey liver microsomal P450 2C9 (an experimental V max /K m value of 1.7 mM min À1 ) and marmoset P450 3A4 (V max /K m of 2.6 mM min À1 ), respectively.…”

“…However, we could image somehow altered catalytic activities of monkey P450 variants having amino acid substations found inside the substrate recognition sites. We experienced fast eliminations of P450 2D-dependent metoprolol and P450 3A-dependent midazolam in limited numbers of cynomolgus monkeys [18] and marmosets [19]. It should be noted that understanding of polymorphic monkey P450 variants in the future would be important for using monkeys in drug development and identification of such P450 2D/3A variants that lead to adverse drug reactions.…”

“…Human P450 cocktail probe metabolic clearance previously described [17] was compared to those of the same cassette dosing in cynomolgus monkeys [18] and marmosets [19] recently. Based on the pharmacokinetics of cynomolgus monkeys and marmosets, simplified human physiologically based pharmacokinetic models for the probe substrates [20,21] could successfully estimate the corresponding human pharmacokinetics.…”

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

“…Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug oxidation activities (Uno et al, 2014a;Utoh et al, 2015), genetic variants have not yet been investigated in marmoset P450 2C19. The pharmacokinetics of the human P450 probes caffeine, warfarin, omeprazole, metoprolol, and midazolam (Turpault et al, 2009) were investigated in mice transplanted with human hepatocytes, marmosets, monkeys, dogs, and minipigs at doses of 1.0 mg/kg to clarify the similarities and occasional species differences (Mogi et al, 2012;Koyanagi et al, 2015;Uehara et al, 2016;Utoh et al, 2016). Racemic warfarin was metabolized to 7-and 6-hydroxywafarin in marmosets in vivo in a similar manner to humans .…”