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.     

Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients

1 Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is being developed for the prevention of rejection following solid organ transplantation. This crossover study investigated the effect of food and antacid (Maalox^® TC) on the plasma pharmacokinetics of MPA and its inactive glucuronide metabolite MPAG after giving single 2  g MMF doses orally to rheumatoid arthritis patients.
2 With food, the AUC of MPA in plasma was equivalent to that following an overnight fast. MPA t _max was slightly delayed and C _max was lowered about 25%, consistent with delay in gastric emptying in the fed state. MPAG C _max and AUC were higher in the fed relative to the fasting state, suggesting more complex processes involving changes in glucuronidation may also be occurring with food.
3 With antacid, AUC of MPA was lowered about 15% compared with fasting and C _max was decreased 37%. Plasma MPAG parameters were similarly reduced. These parallel changes in MPA and MPAG are consistent with reduced absorption.
4 The changes in MPA with both food and antacid are small in comparison with the interpatient variability and are not likely to have clinically major effects; the changes in MPAG are of mechanistic interest.     

A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product

Aims The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration ( C _max ) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.
Methods Limited sampling models (LSM) were developed for CBZ and CBZE following 200–800  mg single oral dose and 400–800  mg twice daily dose for 14 days of a sustained-release product (CBZ-SR) to estimate AUC and C _max. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48  h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state C _min (plasma concentration obtained 5  min before the last CBZ-SR dose).
Results The model provided good estimates of AUC and C _max for CBZ and CBZE. The bias and the precision of the predicted AUC and C _max for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.
Conclusions The method described here may be used to estimate AUC and C _max for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.     

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 age and gender on the pharmacokinetics of eprosartan

Aims To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods Twenty-four subjects (eight subjects/group) received a single 200  mg eprosartan oral dose followed by serial blood sampling over 24  h.
Results Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and C _max values were ≈2-fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; C _max 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and C _max values were, on average, ≈2-fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound C _max 95% CI: 1.02, 4.12]. t _max was delayed in the elderly men compared with young men, with a median difference of 2.5  h (95% CI: 1.00, 3.01  h).
Conclusions No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈  two fold higher AUC and C _max values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200  mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.     

Effect of buffering on pharmacokinetics of ketoprofen enantiomers in man

Aims Concomitant administration of magnesium hydroxide may affect the rate or extent of absorption of non-steroidal anti-inflammatory drugs. In order to find out whether or not buffering modifies the pharmacokinetics of ketoprofen, plasma concentration-time courses resulting from oral administration of unbuffered formulations were compared with those of buffered formulations.
Methods Two groups of 12 healthy and young male subjects were included in two randomized cross-over studies and received single oral doses of ketoprofen 12.5 or 25  mg, respectively, given as tablets which were either unbuffered or buffered with magnesium hydroxide/citrate. Ketoprofen enantiomers in plasma were determined by h.p.l.c. up to 24  h post-dose.
Results Maximum plasma concentrations ( C _max ) of both the (R)- and (S)-enantiomer, observed after administration of the buffered formulations (12.5 and 25  mg), were higher compared with the unbuffered tablets by about 50–80%. The area under concentration-time data (AUC) was unaffected, and, hence, C _max/AUC was increased by buffering. Time to C _max ( t _max ) and mean residence time (MRT) tended to be or was shortened by buffering.
Conclusions It is concluded that buffering of two ketoprofen formulations with magnesium hydroxide/citrate enhanced the concentration maximum by increasing the rate of absorption and leaving AUC unaffected.     

Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers

Aims To study the effect of eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, on digoxin pharmacokinetics in a randomized, open-label, two period, period balanced crossover study in 12 healthy men.
Methods Each subject received a single 0.6  mg oral dose of digoxin (Lanoxicaps^® 0.2  mg/capsule, Glaxo Wellcome) alone or following 4 days of dosing with eprosartan 200  mg orally every 12  h. Each study period was separated by a 14 day washout interval. Serial blood samples were obtained for up to 96  h after each digoxin dose for determination of digoxin pharmacokinetics. The effect of eprosartan on digoxin pharmacokinetics was assessed through an equivalence-type approach using AUC(0, t ') as the primary endpoint.
Results For AUC(0, t '), the ratio of digoxin+eprosartan:digoxin alone was 0.99 with a 90% confidence interval (CI) of [ 0.90, 1.09]. For C _max, the ratio was 1.00 with a 90% CI of [0.86, 1.17]. t _max was similar for both regimens. Both regimens were safe and well tolerated.
Conclusions Based on AUC and C _max data, it can be concluded that eprosartan has no effect on the pharmacokinetics of a single oral dose of digoxin.     

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.     

The effects of age and gender on the pharmacokinetics of irbesartan

Aims Single dose pharmacokinetics and safety of irbesartan, an angiotensin II receptor antagonist, were evaluated in healthy young and elderly male and female subjects.
Methods Irbesartan was administered as two 25  mg capsules after a 10  h fast to 12 young men, 12 young women, 12 elderly men and 12 elderly women. Serial blood and urine sample were collected up to 96  h after the dose. Plasma and urine samples were analysed for irbesartan by h.p.l.c./fluorescence methods.
Results No statistically significant gender effects were observed in peak plasma concentration ( C _max ), area under the curve (AUC), and terminal elimination half-life ( t _1/2 ) of irbesartan. The geometric mean AUC and C _max increased by about 43% and 49%, respectively, in the elderly subjects. Also the time to peak was significantly shorter in the elderly subjects compared with that observed in the young subjects. Renal clearance of irbesartan was significantly reduced in the elderly females but this reduction is not likely to be of any clinical relevance since less than 3% of the administered dose of irbesartan is excreted unchanged in the urine.
Conclusions Although there was an effect of age on the pharmacokinetics of irbesartan, based on the safety and efficacy profile, no adjustment in irbesartan dosage is necessary with respect to age or gender.     

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.     

Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole

Aims  Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole.
Methods  Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days.
Results  When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration ( C _max) and the area under the plasma concentration–time curve of voriconazole (AUC_τ) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole C _max or AUC_τ. Time of C _max ( t _max) elimination half-life ( t _1/2) or terminal phase rate constant ( k _el) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events.
Conclusions  Coadministration of the histamine H₂-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.     

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.     

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.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.     

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers

Aims To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration.
Methods Pranlukast (300  mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30  min after a standard high fat content meal. Blood samples were collected up to 18  h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed.
Results Statistically significant ( P <0.05) increases were noted in AUC(o, t ) (56%) and t _max (2.5  h) after evening administration. C _max was 14% higher after evening dosing (95% C.I. 0.71–1.84).
Conclusions Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.     

Stereoselective interaction between piroxicam and acenocoumarol

1 An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.
2 Eight healthy male volunteers received an oral dose of 4  mg rac -acenocoumarol on days 1 and 8, plus 40  mg piroxicam orally 2  h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24  h interval.
3 The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: C _max+28.0% (s.d.23.8), P <0.05; AUC(0,  24  h)+47.2% (21.5), P <0.005; and t _1/2+38.0% (34.5), P <0.01. A concomitant decrease of CL/ F was observed: −30.8% (10.0), P <0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: C _max: +9.5% (s.d.36.6), AUC(0,  24  h): +15.4% (23.4), t _1/2: +19.9% (42.0), and CL/ F: −9.8% (20.5). V/F remained unchanged for both enantiomers.
4 Piroxicam plasma AUC(0,  24  h) correlated closely with R- and Sacenocoumarol AUCs on day 1 ( r =0.901, P <0.005 and r =0.797, P <0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol ( r =0.903, P <0.001) and S-acenocoumarol ( r =0.711, P <0.05).
5 Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.     

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.     

Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients

Aims Ropinirole is a specific non-ergoline dopamine D₂-receptor agonist with antiparkinsonian properties.The pharmacokinetic parameters of ropinirole taken in the fasted condition were compared with those when it was co-administered with food.
Methods This was an open, randomized, two sessions cross over study in 12 patients with Parkinson's disease, comparing the steady-state pharmacokinetic profiles of ropinirole on two different study days: 'fasted' and 'fed'.
Results The mean C _max was lower in the 'fed' regimen than in the 'fasted' one (−25%, P =0.002). The median t _max was observed 2.6  h later in the 'fed' regimen than in the 'fasted' regimen ( P <0.05). There was a slight but significant decrease in AUC(0,8  h) in the 'fed' regimen ( P =0.03).
Conclusions Food decreases the rate of absorption of ropinirole, but has little effect on the extent of absorption.     

The metabolism of zolmitriptan: effects of an inducer and an inhibitor of cytochrome p450 on its pharmacokinetics in healthy volunteers

Two studies were conducted in healthy volunteers to evaluate the effects of rifampicin and cimetidine on the pharmacokinetics of the oral antimigraine compound zolmitriptan. Each study was an open, randomised, two-period crossover design. Rifampicin 600mg was administered daily for 8 days and cimetidine 400mg was administered three times daily for 2 days. In the control periods, no treatment was given. A single 5mg oral dose of zolmitriptan was given on the last day of each period. Enzyme induction by rifampicin was monitored using 6-beta hydroxycortisol/cortisol ratios. Rifampicin resulted in small (<18%), clinically insignificant decreases in the mean area under the plasma concentration-time curve (AUC), maximum plasma concentration (C(max)) and elimination half-life (t((1/2))) of zolmitriptan and its active metabolite, 183C91. Cimetidine, however, inhibited the metabolism of zolmitriptan and 183C91, increasing the mean C(max) by 16 and 50%, respectively, and increasing the mean AUC by 48 and 105%, respectively. Mean t((1/2)) was prolonged by 2.2 hours for zolmitriptan and by 4.2 hours for 183C91. The tolerability of zolmitriptan was unaltered when it was administered with either drug. Cytochrome 1A2 is likely to be the isoenzyme responsible for the metabolism of zolmitriptan. The increased exposure to zolmitriptan and 183C91 by cimetidine indicated that a reduction in the total daily recommended dose of zolmitriptan may be necessary when treating migraine patients who are taking nonspecific cytochrome P450 inhibitors or specific cytochrome 1A2 inhibitors.     

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.