Model for the drug–drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans

Abstract

1. Anti-human cytochrome P450 (CYP) 3A4 antiserum completely inhibited midazolam metabolism in monkey liver microsomes, suggesting that midazolam was mainly metabolized by CYP3A enzyme(s) in monkey liver microsomes. 2. Midazolam metabolism was also inhibited in vitro by typical chemical inhibitors of CYP3A, such as ketoconazole, erythromycin and diltiazem, and the apparent K(i) values for ketoconazole, erythromycin and diltiazem were 0.127, 94.2 and 29.6 microM, respectively. 3. CYP3A inhibitors increased plasma midazolam concentrations when midazolam and CYP3A inhibitors were co-administered orally. However, the pharmacokinetic parameters of midazolam were not changed by treatment with CYP3A inhibitors when midazolam was given intravenously. This suggests that CYP3A inhibitors modified the first-pass metabolism in the liver and/or intestine, but not systemic metabolism. 4. The drug-drug interaction responsible for CYP3A enzyme(s) inhibition was observed when midazolam and inhibitors were co-administrated orally. Therefore, it was concluded that monkeys given midazolam orally could be useful models for predicting drug-drug interactions in man based on CYP3A enzyme inhibition.

Asymmetric Intestinal First-Pass Metabolism Causes Minimal Oral Bioavailability of Midazolam in Cynomolgus Monkey

“…Thus, most of the midazolam taken up into intestinal tissues is metabolized in monkeys, whereas little is metabolized in rats. This may support the usefulness of cynomolgus monkeys, compared with rats, in predicting drug-drug interactions via CYP3A inhibition and/or induction upon oral administration of midazolam with other drugs, as proposed by Kanazu et al (2004).…”

“…Unlike humans, cynomolgus monkeys show minimal bioavailability of midazolam (approximately 2-6%), even though F h was not small (ϳ66%) (Kanazu et al, 2004;Sakuda et al, 2006). Interestingly, Sakuda et al (2006) recently showed that midazolam is completely absorbed by intestinal tissue in cynomolgus monkey, implying that intestinal metabolism may have a crucial role in the low bioavailability of midazolam (Sakuda et al, 2006).…”

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

“…A recent study suggested that species differences could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process (Komura and Iwaki, 2008;Takahashi et al, 2009;Akabane et al, 2010). For example, minimal oral bioavailability of MDZ in cynomolgus monkeys (2-7%) is not fully explained by hepatic availability (ϳ70%) but is rather attributed to its low intestinal availability (ϳ10%) (Kanazu et al, 2004;Sakuda et al, 2006;Nishimura et al, 2007b;Ogasawara et al, 2007). Thus, CYP3A substrates, such as MDZ, showing a high clearance in monkeys are not suitable as in vivo markers of enzyme induction, because drug-induced up-regulation of CYP3A expression is unlikely to result in any detectable increase in first-pass metabolism of substrates, particularly in the intestine.…”

“…Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009). Furthermore, when an oral dose of CYP3A substrates, such as midazolam (MDZ) and simvastatin, was coadministered with typical CYP3A inhibitors, these monkeys showed markedly higher plasma concentrations than those who received a dose of substrate alone (Kanazu et al, 2004;Ogasawara et al, 2007Ogasawara et al, , 2009a. These findings suggest that monkeys can be used to investigate the underlying mechanism of and to predict the likelihood of clinical DDIs when CYP3A inhibition is involved.…”

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 hepatic metabolism of specific human CYP2C substrates, such as tolbutamide, warfarin, and (S)-mephenytoin, is known to be impaired more in dogs than in humans [13], whereas metabolism studies using liver microsomes demonstrated that the metabolism of human CYP2D substrates, such as bufuralol and dextromethorphan, was similar in humans and dogs [10,11,14]. Monkeys were originally considered to have pharmacokinetic properties similar to those of humans due to genetic similarities, however, previous studies showed that the bioavailability (BA) of some drugs including human CYP3A substrates was markedly lower in monkeys than in humans [7,[15][16][17][18][19][20]. Monkeys have also been shown to exhibit higher CYP activities for human CYP2D6 substrates in their liver microsomes than humans [10,12,16,21,22].…”