P107
THE PRESENCE OF AN ALLELE WHICH CODES FOR FUNCTIONAL CYP3A5
REDUCES THE EFFECT OF AKI ON HEPATIC MIDAZOLAM METABOLISM IN
CRITICALLY ILL PATIENTS
Kirwan, C 1,3 , Philips, B 1 , Morton, M 2 , MacPhee, I 3
1 Departement of Intensive Care,
George’s University of London
2 Analytical Unit, 3 Department of Renal Medicine, St
BACKGROUND: Cytochrome P450 3A (CYP3A), the most abundantly expressed cytochrome
P450 enzymes in liver, are responsible for the metabolism of over 50% of drugs used across several therapeutic classes. In adults, CYP3A is represented primarily by the major isoform,
CYP3A4, and a polymorphically expressed isoform, CYP3A5. Individuals with at least one wild-type CYP3A5*1 allele synthesise functionally active enzyme while homozygotes for the * 3 allele are functional non-expressers of the enzyme. The presence of functional CYP3A5 increases the hepatic metabolism of CYP3A substrates such as tacrolimus. CKD is known to reduce the hepatic metabolism of drugs via the CYP3A enzyme system and we have shown, recently, that AKI has a similar effect and that the length of time with AKI is the most important variable. We hypothesise that expression of functional CYP3A5 may reduce the impact of AKI on hepatic drug metabolism as has been shown to be the case for drug interactions with the imidazole antifungals.
METHODS: 72 (45 male) (mean age 72 range 23-90) critically ill patients with no AKI and varying degrees of severity of AKI were recruited. Midazolam concentration was measured 4 hours after intravenous administration as a probe-drug for hepatic CYP3A 4/5 enzyme activity
(T
4
[midazolam]). This is a validated method for testing CYP3A activity in critically ill patients.
Patients were excluded if they were on any known CYP3A4/5 inhibitors.
RESULTS:
Two patients with severe AKI had
Fig 1
120 unexpectedly high T
4
[midazolam]. Fig 1 demonstrates the following: Without a
80
AA / AG
GG
CYP3A5*1allele, the rate of midazolam metabolism increased with duration of AKI
(r 2 =0.24; p<0.0001) (solid line). Patients
15 who had at least one *1 allele (dashed line) were protected from the inhibitory effect
10 that AKI has on hepatic drug metabolism
(significant difference between the correlation lines p=0.011). If the two major outliers are removed (dotted grey line) from the *3/*3 group (r 2 =0.23; p<0.001), the correlation lines remain statistically different (p=0.048)
5
0
0 50 100 150
Time with AKI (hours)
200
CONCLUSION: The presence of an allele which codes for functional CYP3A5 protects critically ill patients from the inhibitory effect of AKI on the hepatic metabolism of midazolam.