Pharmacokinetics and metabolic elimination of tolbutamide in female rats: Comparison with male rats

As there are to be known gender differences in the expression profiles of rat hepatic CYP2C, we examined the pharmacokinetic behavior of tolbutamide (TB), a typical probe for CYP2C, and hepatic enzyme activities for metabolizing TB in female rats to compare with male rats. On the pharmacokinetic analysis of TB after intravenous administration to female rats, the elimination rate constant at the terminal phase (k_e), total clearance (CL_tot) and the apparent volume of distribution at steady‐state (Vd_ss) were significantly lower than in male rats. The binding rates of TB to serum protein were similar in male and female rats, indicating that the change in unbound TB concentration in serum is not associated with the difference in the pharmacokinetic disposition of TB. On metabolic examination using hepatic microsomes, the maximum reaction velocity (V_max) of the metabolic conversion from TB to 4‐hydroxytolbutamide (4‐OH‐TB) in female rats was lower than that in male rats, although there was no significant difference in the Michaelis constant (K_m) between genders. Consistent with this, the V_max‐to‐K_m ratio (V_max/K_m) was significantly lower in female rats than in male rats. Therefore, the low in vitro CYP2C‐dependent activity for hepatic TB removal in female rats provided a clear explanation for the lower in vivo elimination clearance of TB. Our findings strongly suggest that there is a gender difference in the metabolic capacity to eliminate drugs that serve as substrates of hepatic CYP2C enzymes in rats.     

Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased

Peritoneal dialysis of a highly protein‐bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfamethoxazole treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfadimethoxine treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration‐dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacokinetics of tolbutamide and its metabolite 4‐hydroxy tolbutamide in poloxamer 407‐induced hyperlipidemic rats

Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4‐hydroxy tolbutamide (4‐OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407‐induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration–time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non‐renal clearance (CL_NR). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4‐hydroxylated metabolite formation ratio (AUC_4‐OHTB/AUC_TB) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CL_int (by 28.8%) for metabolism of tolbutamide to 4‐OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CL_int changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state. Copyright © 2014 John Wiley & Sons, Ltd.     

Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil

1.?We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats.

2.?Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (k_e) was significantly decreased without significant change in the volume of distribution at the steady state (Vd_ss).

3.?The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU.

4.?The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU.

5.?These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.     

Enzyme activity analysis of CYP2C18 with exon 5 skipped

AIM: To study the enzyme activity of CYP2C18 variant with exon 5 skipped. METHODS: A full length CYP2C18 cDNA X1 and an exon 5 skipped variant CYP2C18 X2 were separately subcloned into mammalian expression vector pREP9 to transfect HepG2 cells. The expression of CYP2C18 mRNA in transgenic cells and human liver tissues were determined by RT-PCR. The enzyme activity of CYP2C18 to oxidate tolbutamide in postmitochondrial supernate (S9) fraction was determined by HPLC. The cytotoxicity of ifosfamide to transgenic cells was evaluated by MTT test. RESULTS: HepG2-CYP2C18 X1 cells showed strong expression of the full length CYP2C18 mRNA. On the other hand, HepG2-CYP2C18 X2 cells had only infinitesimal expression of the exon-skipped CYP2C18 as well as the full length CYP2C18, while non-transfected HepG2 cell only demonstrated an infinitesimal expression of the full length CYP2C18. The expression of CYP2C18 exons 2 to 7 was also analyzed by RT-PCR in 7 extratumoral liver tissues. Among them, 3 samples expressed on     

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl_nr was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first‐pass effect in NARs than in the controls. Copyright © 2009 John Wiley & Sons, Ltd.     

Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (f_s)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between f_s and the first-order elimination rate constant (k), f_s and total clearance (CL _total ),and f_s and the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f _I )showed twofold variations and were not related to f_s.The half-effective plasma concentrations (C _p50% )of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing f_s.The C_p50% values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to f_s.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of f_s (twofold), k (1.3-fold), V_d (1.5-fold), and CL_total (twofold). The intrinsic clearance (CL _intr )remained unaffected. There was no significant increase of f_L but a twofold increase of the L/P ratio. AE/dose and the C_p50% values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.This work was supported by the Deutsche Forschungsgemeinschaft: it is part of the Ph.D. thesis for D. T.     

Change in pharmacokinetic behavior of intravenously administered midazolam due to increased CYP3A2 expression in rats treated with menthol

Menthol is used widely as a constituent of functional foods and chemical drugs. The present study investigated changes in the pharmacokinetic behavior of intravenously administered midazolam (MDZ), a probe for CYP3A, when rats were treated with menthol. The study also examined which isoforms of CYP3A1 and 3A2 were menthol‐inducible and contributed to the altered disposition of midazolam. Menthol was administered intraperitoneally to rats once daily for 3 days at a dose of 10 mg/kg, while the control rats received vehicle alone. The pharmacokinetic examination of i.v. administered midazolam revealed that serum midazolam concentrations at each sampling point were lower in the menthol‐treated rats than in the control rats. Regarding the pharmacokinetic parameters of the menthol‐treated group, the area under the curve (AUC) was decreased significantly and, correspondingly, the elimination rate constant at terminal phase (k_e) was increased significantly without significant changes in the volume of distribution at steady state (Vd_ss). The metabolic production of the 1′‐hydroxylated and 4′‐hydroxylated forms of MDZ by hepatic microsomes was significantly greater in the menthol‐treated rats than in the control rats. The expression levels of mRNA and protein for hepatic CYP3A2 were more than 2.5‐fold higher than the control levels when the rats were treated with menthol, whereas no changes were observed in the expression levels of CYP3A1. These results indicate that menthol enhanced the elimination clearance of midazolam by inducing hepatic CYP3A2 and that careful attention should be paid when menthol is ingested in combination with drugs that act as substrates for CYP3A. Copyright © 2014 John Wiley & Sons, Ltd.     

Changes in renal clearance of furosemide due to changes in renal blood flow and plasma albumin concentration

Summary We have shown that, within therapeutic plasma concentrations, the unbound fraction of furosemide changes in direct proportion to the reciprocal of the plasma albumin concentration (correlation coefficient 0.99). Changes in the albumin concentration were produced by ultrafiltration of human plasma using a haemofiltration filter. Thus, we propose that, when studying changes in the pharmacokinetics of a highly protein bound drug, calculated changes in the unbound fraction offer an alternative to actual measurement of the unbound concentration, which is often difficult.Nine healthy volunteers receiving a continuous furosemide infusion were studied in normovolaemia and after dehydration (–1.4 kg), with and without pretreatment with an angiotensin converting enzyme inhibitor (captopril) or an a₁-adrenoceptor blocking agent (prazosin). Significantly larger changes in the renal clearance of furosemide were found that could be explained by changes in the unbound fraction. Following dehydration, the unbound fraction of furosemide was decreased by about 5%, while its renal clearance fell by 27%, 33% and 13% after pretreatment with placebo, captopril and prazosin, respectively. The secretory clearance of the unbound furosemide changed substantially and in parallel with changes in the renal blood flow. It is suggested that changes in the renal clearance and excretion of furosemide and its t_1/2 are much more dependent on changes in renal blood flow than on changes in its unbound fraction.     

Effects of water deprivation on the pharmacokinetics of metformin in rats

It was reported that metformin was mainly metabolized via hepatic CYP2C11, 2D1 and 3A1/2 in rats, and in a rat model of dehydration, the expressions of hepatic CYP2C11 and 3A1/2 were not changed. Hence, it could be expected that the Cl(nr) of metformin is comparable between two groups of rats if the contribution of CYP2D1 in the rat model of dehydration is not considerable. It was also reported that the timed-interval renal clearance of metformin was dependent on the urine flow rate in rats. In the rat model of dehydration, the 24 h urine output was significantly smaller than in the controls. Hence, the urinary excretion of metformin was expected to be smaller than the controls. The above expectations were proven as follows. After intravenous administration of metformin (100 mg/kg) to the rat model of dehydration, the Cl(nr) were comparable between the two groups of rats. After both intravenous and oral administration of metformin (both 100 mg/kg) to the rat model of dehydration, the 24 h urinary excretion of the drug was significantly smaller than in the controls. After oral administration of metformin to the rat model of dehydration, the AUC was significantly greater (99.2% increase) than the controls.     

Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance

Summary Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggest that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.     

The pharmacokinetics of escitalopram in patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of escitalopram was determined by means of nonlinear mixed effect modeling, considering both the Child-Pugh classification (and its components) and cytochrome P450 2C19 (CYP2C19) activity. Twenty-four subjects were grouped according to their Child-Pugh score as healthy, with mild hepatic impairment or with moderate hepatic impairment. The subjects were administered a single oral dose of escitalopram 20 mg, and blood was sampled up to 168 hours after dosage. The serum concentration of escitalopram was determined and the pharmacokinetics assessed by nonlinear mixed effect modeling. The CYP2C19 activity was measured from the urinary excretion ratio of S/R-mephenytoin. All subjects tolerated the treatment well, and no serious adverse events were reported. Predicted mean area under the curve from zero to infinity (AUC(inf)) values were 51% and 69% higher for patients with mild and moderate hepatic impairment (Child-Pugh classification), respectively, compared with healthy subjects. The best-fitting model showed an influence of CYP2C19 activity on clearance and body weight on the volume of distribution for escitalopram. CYP2C19 activity is a better predictor of escitalopram clearance than is Child-Pugh classification.     

Pharmacokinetics of lansoprazole in Chinese healthy subjects in relation to CYP2C19 genotypes

AIM: To study the kinetic characteristics of lansoprazole in healthy Chinese subjects in relation to CYP2C19 genotype status for the individualized dose regimen of lansoprazole. METHODS: Nine homozygous extensive metabolizers (homo EMs) and 9 poor metabolizers (PMs) were recruited for the study from a total of 70 healthy Chinese volunteers, whose CYP2C19 genotype status was determined by the PCR-RFLP techniques. After a single oral dose of 30 mg lansoprazole capsule, plasma concentrations of lansoprazole were determined with HPLC method. RESULTS: In Chinese subjects, the allele frequencies of the CYP2C19ml and CYP2C19m2 mutation were 0.35 and 0.07, respectively. The concentration-time curves in the two groups were best fitted to a one-compartment model. In the homo EMs and the PMs groups, the main kinetic parameters were as follows: Tmax (2.44±0.85) and (2.33±0.94) h, Cmax(1.10±0.34) and (1.73±0.56) mg/L, Cl/F (16.55±6.38) and (3.58±1) L/h, T1/2ke(1.96±0.51) and (4.21±0.53) h, AUC were (3.23±1.0     

毛冬青胶囊对大鼠体内细胞色素P450 代谢活性的影响*

目的：采用Cocktail探针药物法研究毛冬青胶囊对大鼠CYP1A2、CYP3A2、CYP2C6、CYP2D1、CYP2D2和CYP2E1体内代谢活性的影响。方法：分别以茶碱、咪达唑仑、甲苯磺丁脲、奥美拉唑、右美沙芬和氯唑沙宗作为探针底物,将大鼠随机分为3组：空白对照组、毛冬青的低剂量组和高剂量组。低、高剂量组每日分别灌胃给予毛冬青胶囊1.8、3.6 g·kg-1,空白对照组每日给予与低剂量组等体积的生理盐水,各组均为1次/天,连续14 d。各组分别于第15天给予Cocktail探针药物,于给药前、后不同时间点取血,用LC-MS/MS检测各探针药物的血药浓度,计算药代动力学参数。结果：茶碱低剂量组cmax、AUC0-t有极显著差异（P≤0.01）;甲苯磺丁脲高剂量组和氯唑沙宗低剂量组AUC0-t有显著差异（P≤0.05）;其他无统计学差异。结论：毛冬青胶囊对大鼠体内CYP2C6和CYP1A2有强诱导作用,对CYP2E1有中强诱导作用,其他亚型基本无影响。     

Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite,N‐desmethylsildenafil,in rats in vitro and in vivo

Objectives It has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N‐desmethylsildenafil, in humans. However, in‐vivo studies in rats have not been reported. Methods Sildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In‐vitro studies using rat liver microsomes were also performed. Key findings The area under the plasma‐concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N‐desmethylsildenafil (0–4 h): sildenafil (0–∞) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in‐vitro study using rat liver microsomes. Conclusions Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N‐desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N‐desmethylsildenafil in humans.     

Pharmacokinetics of verapamil and its metabolite norverapamil in rats with hyperlipidaemia induced by poloxamer 407

1. In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10?mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats).

2. The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats.

3. The AUC of norverapamil and AUC_norverapamil/AUC_verapamil ratios following intravenous and oral administration of verapamil were unchanged in HL rats.

4. Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.

     

Effects of obesity induced by high‐fat diet on the pharmacokinetics of nelfinavir,a HIV protease inhibitor,in laboratory rats

The effect of obesity induced by a high‐fat diet on the pharmacokinetics (PK) of nelfinavir (NFV) was investigated, focusing on the change of distribution and elimination caused by dyslipidemia and hepatic steatosis. The plasma unbound fraction (f_u) of NFV in obese rats (0.61±0.03%) was significantly lower than in the control (1.10±0.09%), caused by increasing the plasma triglyceride‐rich lipoprotein level. After intravenous (i.v.) administration of NFV, the marked decrease of the distribution volume and slower total clearance (39.5% and 69.1% of the control, respectively) caused by the lower f_u were the main reasons for the significantly higher area under the blood concentration versus time curve (AUC) in obese rats (145.3% of the control). The absorption of NFV after intraduodenal (i.d.) administration in obese rats was significantly greater than in the control (AUC; 170.4% of the control). The increased bile in obese rats was the main reason for the increasing absorption of NFV, and the lower expression of intestinal P‐glycoprotein was also considered. On the other hand, although higher AUCs in obese rats were shown, unbound AUCs in the obese rats were slightly lower than in the control, namely, the plasma NFV concentration in obese rats to obtain the same pharmacological effect was higher than in the control, suggesting the difficulty of drug monitoring. These results suggest that it is necessary to pay further attention to therapeutic drug monitoring of NFV in patients manifesting metabolic syndrome, such as dyslipidemia and visceral fat accumulation, including hepatic steatosis. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacokinetics of phenytoin and its metabolite, 4'-HPPH, after intravenous and oral administration of phenytoin to diabetic rats induced by alloxan or streptozotocin

It has been reported that diabetic patients have an increased risk of developing epileptic convulsions compared with the non-diabetic population, and phenytoin has widely been used for neuralgia in diabetic neuropathy. It has also been reported that in both diabetic rats induced by alloxan (DMIA rats) and by streptozotocin (DMIS rats), the protein expression and mRNA level of 2C11 decreased, but in DMIS rats, the protein expression of CYP2C6 increased. Thus, the pharmacokinetics of phenytoin and 4'-HPPH were investigated after intravenous or oral administration of phenytoin at a dose of 25 mg/kg to DMIA and DMIS rats. After intravenous or oral administration of phenytoin, the AUC (or AUC(0-12 h)) values of both phenytoin and 4'-HPPH were comparable (not significantly different) between each diabetic and the respective control rats. Although the exact reason is not clear, this could have been due to opposite protein expression (and/or mRNA levels) of CYP2C6 and 2C11 in diabetic rats.     

Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam,a drug of high intrinsic clearance,in the isolated perfused rat liver preparation

The influence of protein binding on the extraction ratio, and availability, of diazepam has been examined in the single-pass isolated perfused rat liver preparation. Binding of diazepam was varied by adjusting the concentration of albumin in the perfusate. In the absence of binding the extraction ratio of diazepam was high, 0.93–0.995. Extraction decreased dramatically as the degree of binding was increased. The data are more consistent with the parallel-tube model than with the well-stirred model, two perfusion models that have been used to describe hepatic drug elimination.     

Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes,including CYP2B6, CYP2C9 and CYP2C19

Aim

Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes.

Methods

We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted.

Results

Predicted mean post-partum to second trimester (PP : T₂) ratios of methadone AUC, C_max and C_min were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T₃) ratios of methadone AUC, C_max and C_min were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T₃ ratios of glyburide AUC, C_max and C_min were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively.

Conclusions

Our PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes.