TAC is a well-known CYP3A substrate, and its concentration can be influenced by both function of the liver and presence of CYP3A inhibitors and inducers [9]. Additionally, TAC is a P-glycoprotein (P-gp) substrate and may therefore be affected by P-gp inhibitors/inducers [10]. In our case, no significant changes were observed in liver function following the initiation of DEX treatment. In addition to DEX, concomitant medications such as APR and fluconazole can influence CYP3A activity. The patient consistently took 200 mg/day fluconazole while on TAC. Fluconazole is indeed classified as a moderate CYP3A inhibitor [6]. However, considering that the patient was taking the medication concurrently for an extended period, the impact of any fluctuations in TAC concentration was expected to be minimal. APR exhibits both inhibitory and inductive effects on CYP3A activity. In a study involving 12 healthy adults, oral administration of APR at 125 mg on day 1 and 80 mg on days 2–3 was followed by intravenous administration of 2 mg midazolam on days 4, 8, and 15. The area under the blood concentration curve (AUC) ratio for midazolam was 1.25 on day 4, 0.81 on day 8, and 0.96 on day 15 [11]. As these data were obtained after intravenous midazolam administration, it is expected that both inhibition and induction would be affected more when midazolam is administered orally because of the influence of the first-pass effect. APR is also an inducer of CYP2C9 [11], and Ohno et al. reported that its induction effect was observed approximately 2 weeks after the start of APR administration and generally recovered after 3 weeks [12, 13]. The mechanisms of induction of CYP3A and CYP2C activities are generally considered to be similar, and the duration of their induction depends on the turnover rate of the CYP enzymes [14, 15]. In the present case, the TAC C/D ratio decreased approximately 2 weeks after APR administration, with both R-HyperCVAD and R-MA treatments, and then began to increase. These findings suggest that the variation in the TAC C/D ratio in the present case can be attributed mainly to the CYP3A activity-inducing effect of APR. The possibility that the induction effect of DEX also contributes to this phenomenon cannot be ruled out. However, the fact that the TAC C/D ratio increased during DEX administration on days 11–14 of R-HyperCVAD treatment suggests that the effect, if any, is not substantial. Using Horn et al.'s Drug Interaction Probability Scale (DIPS), the interaction with DEX was rated as doubtful. However, the interaction with APR was rated as probable [16].

This case study had some limitations. Induction of CYP activity by DEX is mediated by the pregnane X receptor (PXR/NR1I2), whereas PXR/NR1I2 polymorphisms have been reported to affect DDIs of steroids and TAC [17]. Additionally, CYP3A5 polymorphisms are known to influence the pharmacokinetics of TAC [10, 18]. These findings imply that the extent of CYP activity induction by DEX may vary depending on the genetic background; however, information regarding these genetic polymorphisms was not available in this case.

Steroids other than DEX used in this case were methylprednisolone (40 mg/day on days 2–4) during R-MA therapy and methylprednisolone 2 mg/day throughout the duration of TAC administration, but the former was only administered for 3 days and the latter at a lower dose. Therefore, the effect on TAC concentration was considered to be minimal.

Doxorubicin and vincristine, administered in this case as part of the chemotherapy regimen, have been reported to be substrates for CYP3A and P-gp in in vitro studies [19,20,21]. Doxorubicin has also been reported to mildly increase the AUC of docetaxel, a substrate for both CYP3A4 and P-gp, by 50–75% [22]. On the contrary, in a study comprising nine patients treated with chemotherapy regimens containing doxorubicin or vincristine in combination with verapamil, a typical substrate for both CYP3A4 and P-gp, a decrease in AUC was reported in all but one patient, which might have been due to gastrointestinal mucosal damage [23]. No other drug interaction trials have been conducted with these anticancer drugs and CYP3A or P-gp substrate probe. Hence, the impact of these anticancer agents as CYP3A/P-gp inhibitors on the in vivo pharmacokinetics of tacrolimus remains unknown.

Furthermore, although hematocrit levels and inflammatory responses are known to influence the pharmacokinetics of TAC [24,25,26], no association was observed between the C/D ratio of TAC and the course of hematocrit and C-reactive protein levels (an inflammatory response marker) in the present case.

Recently, Hibino et al. reported that CYP3A activity increases on days 4–8 in patients taking DEX and APR [27]. As mentioned earlier, APR has both CYP3A activity-inhibitory and -inducing effects. In an interaction study on midazolam, the AUC of midazolam increased on day 4 and decreased on day 8 [11]. Therefore, the relatively early increase in CYP3A activity reported by Hibino et al. [27] may be partially attributed to DEX. On the contrary, one of the possible reasons for the increase in TCR C/D to 4.4 on day 4 of the second course of R-MA therapy in the present case may be that inhibition was more significant than induction, as APR was administered for only 3 days.

McCune et al. reported the dose-dependent induction of CYP3A activity in human hepatocytes treated with 2–250 µM DEX; however, CYP3A activity-inducing effect was not observed at levels below 1 µM. Considering that the average blood concentration of DEX at 0.5–3.0 h after 16 mg/day oral administration is 0.1 µM, [2] the blood concentration of DEX intravenously administered at 33 mg/day (oral bioavailability of approximately 80% [28], equivalent to 40 mg/day orally) would be approximately 0.25 µM. Moreover, the concentration of the unbound form would be even lower, which is consistent with the fact that the CYP3A activity-inducing effect was not strong in this case.

Although DEX at moderate doses has been reported to result in mild induction of CYP3A activity in erythromycin breath tests, these reports are highly variable [2, 8]. Moreover, no clinical trial has examined the effect of moderate or higher doses of DEX on blood concentrations of typical CYP3A substrate drugs, and conducting such a trial in the future would be ethically unlikely. Therefore, this case, in which high-dose DEX was combined with TAC, out of clinical necessity, is valuable as it suggests that the CYP3A activity-inducing effect of high-dose DEX is not significant.

In conclusion, the C/D ratio trend of TAC in this case suggested that the CYP3A activity-inducing effect of high-dose DEX was not strong. The pharmacokinetic information on DEX and the results of an in vitro enzyme activity-induction study also support the notion that the CYP3A activity-inducing effect of high-dose DEX is not substantial.