Impact of OATP1B1, MDR1, and CYP3A4 Expression in Liver and Intestine on Interpatient Pharmacokinetic Variability of Atorvastatin in Obese Subjects

Abstract

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

“…Consistent with in vitro and clinical drug-drug interaction findings to date (1,(5)(6)(7), data from the current investigation support the hypothesis that doravirine does not have a clinically meaningful effect on CYP3A4 metabolism or OATP1B1, MDR1, and BCRP transporters, which are implicated in the disposition of atorvastatin (13,14). This observation was justified by the lack of changes in exposure, clearance, and half-life associated with atorvastatin when it was administered both alone and concomitantly with doravirine.…”

“…3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are a mainstay in treatment, with atorvastatin being a commonly prescribed agent. Atorvastatin undergoes hepatic metabolism and is a substrate of the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1); P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1); and BCRP (13,14). Similarly to doravirine, atorvastatin is metabolized by CYP3A4 (13), and CYP3A4 modulators have demonstrated a marked effect on its pharmacokinetics (PK) (15).…”

Midazolam Pharmacokinetics in Morbidly Obese Patients Following Semi-Simultaneous Oral and Intravenous Administration: A Comparison with Healthy Volunteers

“…While these results indicate a lack of change in absolute hepatic CYP3A-mediated metabolism of midazolam in morbidly obese individuals, the results are in contrast with our expectations of a lower midazolam clearance in morbidly obese patients which was based on reports in in vitro and animal studies [4–7] and on oral clearance of CYP3A substrates in studies in obese subjects [13, 14]. Assuming that indeed the relative CYP3A activity per unit of liver is reduced in morbidly obese patients [12], we hypothesize that this effect may be counteracted by a higher liver volume [34], resulting in a similar absolute hepatic CYP3A metabolizing capacity in both groups. In agreement with this hypothesis, Greenblatt et al [15] also found no significant difference in absolute CL of midazolam between normal weight (66 ± 2 kg) and obese subjects (117 ± 8 kg) (0.53 ± 0.04 vs. 0.47 ± 0.04 L/min, respectively).…”

“…We anticipate that the increase in oral bioavailability in morbidly obese patients found in our study may be due to reduced CYP3A-metabolizing activity in the intestines. Ulvestad et al [12] found in a study with 19 obese individuals [median BMI 45 (34–59) kg/m 2 ] that CYP3A4 protein expression in the small intestine and liver is lower with increasing BMI. Another possible cause of increased bioavailability is an increase in splanchnic blood flow, which has been reported before in morbidly obese patients.…”

“…CYP3A is an important enzyme system that is responsible for the primary metabolism of 25 % of all clinically used drugs [10], including many drugs that are relevant for obese patients, such as statins (HMG-CoA reductase inhibitors), cardiovascular drugs, antipsychotics, and oncolytic drugs [11]. In obese compared with non-obese subjects, it was shown that hepatic and intestinal CYP3A protein expression decreased with increasing BMI [12] and that oral clearance (CL/ F ) of CYP3A substrates such as triazolam, carbamazepine, and taranabant was lower [13, 14], even though a similar systemic clearance (CL) was found in obese individuals for midazolam [15]. An explanation for the reduction in CYP3A activity upon obesity could be an increased state of inflammation caused by infiltration of macrophages and adipocytes into the adipose tissue excreting inflammation markers and adipokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α [16–18].…”