A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma

Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma.
Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40  mg (MP equivalents) i.v. 6 hourly for 48  h. The bio-conversion and disposition of a 40  mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase.
Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0  h⁻¹ vs 5.5  h⁻¹ respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7  h vs 3.0  h), steady-state AUC (2007.0  ng  ml⁻¹  h vs 2321.0  ng  ml⁻¹  h) and steady-state C _max (698.4  ng  ml⁻¹ vs 647.8  ng  ml⁻¹ ) for MP suleptanate and MP succinate respectively.
Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.     

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients

Aims To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10  mg) and after 28 days therapy with imidapril 10  mg once daily.
Methods C _max, t _max, t _1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation.
Results The AUC of imidapril was 140 (43  s.d.)  ng  ml⁻¹ h after the first dose and 123 (34  s.d.)  ng  ml⁻¹ h at steady state. AUC of the active moiety imidaprilat averaged 211 (101  s.d.)  ng  ml⁻¹ h after the first dose and 240 (55  s.d.)  ng  ml⁻¹ h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22  mmHg after the first dose and 25  mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an E_max-curve, whereas the plateau around E_max is maintained at steady state.
Conclusions In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

Pharmacokinetics of the individual enantiomers of vigabatrin in neonates with uncontrolled seizures

The antiepileptic drug vigabatrin (VGB) is a selective irreversible inhibitor of GABA-transaminase. It is administered as a racemic R(−), S(+) mixture, but the pharmacological activity of vigabatrin resides in the S(+) enantiomer and the R(−) enantiomer is inactive. The pharmacokinetic parameters of the two enantiomers have been studied after administration of a single oral 125  mg dose of the racemate to six neonates. The mean values of C _max and AUC of the S(+) enantiomer were significantly lower ( C _max : 14.0±4.3  mg l⁻¹; AUC: 143±44  mg l⁻¹  h) than those of the R(−) enantiomer ( C _max: 34.1±9.5  mg l⁻¹; AUC: 231±88  mg l⁻¹  h), whereas no significant difference in the time to reach C _max (S(+): 2.1±1.1  h; R(−): 2.2±1  h) was observed between the two enantiomers. During chronic administration (125  mg twice daily over 4 days), there was no evidence of accumulation of either enantiomer.     

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application

Aims The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×10⁶  IU  m⁻² once daily and group B 10×10⁶ IU  m⁻² twice daily (every 12  h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated.
Results The mean area under the serum concentration-time curve to 24  h (AUC(0,24  h)) was 627  IU  ml⁻¹  h in treatment group A and 1130  IU  ml⁻¹  h ( P =0.029) in treatment group B. In both study groups C _max and AUC(0,12  h) were not significantly different. Seventy-two  hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly ( P =0.016), and sIL-2R levels over 1200  pmol  l⁻¹ seemed to reduce the AUC.
Conclusions In patients with metastatic renal cell cancer administration of 20×10⁶  IU  m⁻² of rhIL-2  s.c. in two daily doses (10×10⁶  IU  m⁻² every 12  h) provides better bioavailability and is preferable to the single dose administration.     

No effect of short-term omeprazole intake on acenocoumarol pharmacokinetics and pharmacodynamics

Aims To investigate the effect of omeprazole on the pharmacokinetics of R- and S-acenocoumarol and on their combined anticoagulant activity.
Methods Eight healthy male subjects completed a double-blind, randomized, placebo-controlled, two-way cross-over study. Subjects were given either omeprazole 40  mg or placebo once daily for 3 days. On day 2 of each study period, a single 10  mg oral dose of racemic acenocoumarol was administered and venous blood samples were collected for pharmacokinetic and pharmacodynamic assessments. A wash-out period of 2 weeks separated the two study periods.
Results The pharmacokinetics of R- and S-acenocoumarol (AUC 3016±221 and 233±14  ng  ml⁻¹ h, respectively) did not change after omeprazole (AUC 2929±256 and 220±18  ng  ml⁻¹ h, respectively). Anticoagulant activity (INR_max 1.7±0.1) was unaffected by co-administration of omeprazole (INR_max 1.7±0.1).
Conclusions The short-term intake of omeprazole does not affect acenocoumarol pharmacokinetics or pharmacodynamics. These data differ from the results of previous studies on the effect of omeprazole on warfarin, suggesting a different in vivo interaction profile of omeprazole on acenocoumarol than on warfarin. Drug interaction studies with oral anticoagulants should not be restricted to the use of warfarin.     

The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers

Aims   To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.
Methods   This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.
Results   Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml^{− 1} h with placebo to 1199 ng ml^{− 1} h with ketoconazole. Mean C _max increased by 34%, from 89 ng ml^{− 1} to 119 ng ml^{− 1}, respectively. The treatment effect on both of these parameters was statistically significant ( P < 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.
Conclusions   The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.     

Concentrations and effects of zopiclone are greatly reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied.
Methods In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600  mg rifampicin or placebo once daily for 5 days. On the 6th day, 10  mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10  h.
Results The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5–22.5%) of that after placebo (86.1±34.5  ng  ml⁻¹ h vs 473±114  ng  ml⁻¹  h (mean±s.d.); P <0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9±27.2  ng  ml⁻¹ to 22.5±6.0  ng  ml⁻¹ ( P <0.001) and the half-life from 3.8±0.6  h to 2.3±0.9  h ( P <0.005). A significant ( P <0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment.
Conclusions The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.     

Decreased oral availability of cyclosporin A at second administration in humans

Aims The objective of this study was to determine the extent of period effect on the pharmacokinetics of cyclosporin A (CsA) during consecutive dosing.
Methods Sandimmune Neoral^® and Neoplanta^® capsules were administered to twenty-four healthy Korean male subjects at a single CsA dose of 175  mg in a 2×2 crossover investigation with a 2-week wash-out phase. Concentrations of CsA in blood were measured by a r.i.a. method for a period of 48  h.
Results The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there is a significant ( P <0.01) period effect in AUC(0,last) (area under the blood concentration-time curve above the assay limit) and C _max (maximum blood concentration) between the administrations. A 6 and 9% decrease in the AUC(0,last) and C _max , respectively was seen at the second administration.
Conclusions This period effect on the pharmacokinetics of CsA may be relevant for the patients who need consecutive administration of the drug.     

Clonidine and or adrenaline decrease lignocaine plasma peak concentration after epidural injection

Clonidine is an α₂-adrenoceptor agonist increasingly used in combination with lignocaine for spinal or epidural anaesthesia because of a prolonged analgesic effect. Like adrenaline, it may decrease lignocaine peak concentration ( C _max), thus leading to decreased toxicity. However, the effects of clonidine on resorption of lignocaine into the systemic circulation from the epidural space remain to be established. We studied the pharmacokinetics of lignocaine after epidural injection of lignocaine with or without clonidine, adrenaline and both drugs. Total body clearance and apparent volume of distribution were similar in the four groups, but the maximum observed concentration ( C _max) was markedly increased in the plain solution group as compared with the other groups: (plain lignocaine: 7.15±2.04  μg  ml⁻¹, lignocaine+adrenaline: 3.11±136  μg  ml⁻¹, lignocaine+clonidine: 4.48±1.26 μg  ml⁻¹, lignocaine+adrenaline+clonidine: 4.06±1.42  μg  ml⁻¹ [mean±s.d.]). Our results show that, clonidine decreases lignocaine C _max to the same extent as adrenaline.     

Concentrations and effects of buspirone are considerably reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated.
Methods In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600  mg rifampicin or matched placebo once daily for 5 days. On day 6, 30  mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10  h.
Results The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3–14.5%) of that after placebo (1.64±0.35  ng  ml⁻¹ h vs 22.0±15.1  ng  ml⁻¹ h (mean±s.d.); P <0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6±3.7  ng  ml⁻¹ to 0.84±0.23  ng  ml⁻¹ ( P <0.01) and the half-life from 2.8±0.7  h to 1.3±0.5  h ( P <0.01). A significant ( P <0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment.
Conclusions The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.     

Midazolam pharmacokinetics following intravenous and buccal administration

Aims Midazolam has good anxiolytic qualities and is a well established premedication agent before anaesthesia or short surgical procedures. The objective of the present study was to determine pharmacokinetic data from individual plasma concentration profiles obtained following intravenous and buccal administration of midazolam.
Methods Eight young healthy volunteers received single doses of 5  mg midazolam i.v. and after a period of 1 week buccally in a cross over manner. Blood samples were obtained up to 480  min. The measurement of plasma midazolam concentrations was by gas-chromatography.
Results The maximum plasma concentration was 55.9  ng  ml⁻¹ (range 35.6–77.9  ng  ml⁻¹ ) at 30  min (range 15–90  min) following buccal administration. AUC was calculated to be 15 016  ng  ml⁻¹ min (s.d. 3778  ng  ml⁻¹ min) following i.v. and 11191  ng  ml⁻¹ min (s.d. 1777  ng  ml⁻¹ min) following buccal midazolam. This gave a mean midazolam bioavailabilty of 74.5%.
Conclusions The pharmacokinetic data presented in this study demonstrate a high bioavailability and reliable plasma concentrations following buccal midazolam. The clinical benefit of buccal midazolam may be in particular patient controlled premedication or sedation in adults.     

Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers

Aims To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults.
Methods In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240  min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique.
Results The maximal plasma cobalamin concentration ( C _max ) after nasal administration of 750  μg hydroxocobalamin was 1900±900  pmol  l⁻¹ (mean±s.d.). The maximal plasma cobalamin concentration was reached in 35±13  min ( t _max ). The C _max after nasal administration of 1500  μg hydroxocobalamin was 3500±2500  pmol  l⁻¹ with a t _max of 28±16  min. Both the AUC(0,240  min) and AUC(0,00) increased significantly with an increase of the dose from 750  μg to 1500  μg ( P =0.037 and P =0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted.
Conclusions The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.     

Transplacental distribution of salbutamol enantiomers at Caesarian section

Aims To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section.
Methods Five women about to undergo elective Caesarian section were administered a single 0.25  mg bolus intravenous dose of (R,S)-salbutamol. The time from drug administration to delivery was different for each woman (27–105  min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography.
Results The concentrations (mean±  s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46±0.35 and 0.89±0.50  ng  ml⁻¹, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12–0.74  ng  ml⁻¹ ). The corresponding concentrations of the (S) enantiomer of 0.92±0.45 and 1.11±0.67  ng  ml⁻¹, respectively, were not significantly different (95% CI of the difference −0.08–0.48  ng  ml⁻¹ ). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma ( P =0.016).
Conclusions Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental-foetal metabolism.     

Enhanced effect of triazolam with diltiazem

Aims Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans.
Methods We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25  mg dose of triazolam, a 0.25  mg dose of triazolam after a 3-day treatment of diltiazem (180  mg day⁻¹), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24  h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8  h.
Results Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0±2.4 to 18.2±3.1  ng  ml⁻¹  h; P <0.001; mean±s.d.). Peak triazolam concentration was increased (2.1±0.7 to 3.6±1.0  ng  ml⁻¹, P <0.05) and the elimination half-life prolonged (4.1±2.1 to 7.6±1.9  h; P <0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group.
Conclusions Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid

Aims  To evaluate the effects of cimetidine and Maalox^® (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone.
Methods   Eleven healthy young subjects aged 18–45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co‐administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co‐administered with oral Maalox^®.
Results   The administration of cimetidine increased the ziprasidone AUC(0,∞) by 6% but there were no statistically significant differences in C _max, t _max or λ_z between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox^® did not produce any statistically significant differences in AUC(0,∞), C _max, t _max or λ_z between the ziprasidone+Maalox^® group and the ziprasidone group.
Conclusions   The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox^®. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.     

Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers

Aims To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in  healthy female volunteers.
Methods This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50  μg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16  days of every 12  h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48  h after each dose and for plasma ritonavir on Day 29 at 0 and 4  h postdose.
Results Statistically significant decreases in ethinyl oestradiol mean C _max (−32%) and mean AUC (−41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17  h to 13  h during concomitant ritonavir. No statistically significant change was noted in t _max. The ratios of means (95% confidence intervals) for C _max and AUC were 0.682 (0.612–0.758) and 0.595 (0.506–0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450  hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4  μg  ml⁻¹ were observed at 0 and 4  h postdose, respectively.
Conclusions Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.     

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans

1 Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.
2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N -demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms.
3 After a single, oral 30  mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes.
4 The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL C _max 59  nmol l⁻¹ and AUC (0, t h) 144  nmol l⁻¹h, mean MDL C _max 183  nmol l⁻¹ and AUC 2627  nmol l⁻¹h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C _max 356  nmol l⁻¹ and AUC 10512  nmol l⁻¹h, MDL concentrations below limit of quantitation).
5 We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.     

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V _max /K _m ratio of 0.50–7.26  μl  min⁻¹  mg ⁻¹ protein.
2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K _i of 201±89  μm was obtained for the 3HDZ pathway ( K _m /K _i ratio of 3.0±0.9).
3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K_is of 121±45 and 188±73  μm respectively ( K _m /K _i ratios of 5.2±2.3 and 3.3±1.5 respectively).
4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.     

Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A

Aims In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N -demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N -demethylation of IMI.
Methods Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250  mg daily for 2 days before a single oral dose of 100  mg IMI was administered.
Results Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971±938 vs 3134±2000  μg l⁻¹  h, 95% confidence interval for difference between means: 218 to 2108  μg  l⁻¹  h, P <0.05) and decreased its oral clearance by 30% (60.9±27.4 vs 42.5±22.7  l h⁻¹, 95% confidence internal for difference between means: 7.2 to 31.7  l h⁻¹, P <0.05).
Conclusions We conclude that CYP3A may play an important role in the in vivo N -demethylation of IMI.