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.     

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.     

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.     

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.     

The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90)

Aims Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT_1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan.
Methods A double-blind, randomized, crossover study of the effects of pre-treatment with propranolol 160  mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10  mg dose of zolmitriptan in 12 healthy volunteers.
Results Propranolol increased mean zolmitriptan C _max and AUC by 56% and 37% respectively; mean t _1/2 was prolonged from 3.1 to 4.0  h. Mean C _max and AUC of the pharmacologically active N -desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUC_m/AUC_p ) fell from 0.46 to 0.26. Mean C _max and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUC_m/AUC_p from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11  mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response.
Conclusions The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.     

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.     

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.     

Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients

Aims In renal allograft recipients, trimetazidine (Vastarel^® ) was proposed to be associated with the classic immunosuppressant treatments because it displays anti-ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun^® , and trimetazidine.
Methods Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40  mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin-2 and soluble interleukin-2 receptor levels were measured.
Results The data showed that neither cyclosporin A blood pharmacokinetic parameters, C _max, t _max , AUC, nor the concentrations of interleukin-2 and soluble interleukin-2 receptors were significantly modified.
Conclusions Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.     

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.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

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.     

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.     

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.     

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.     

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.     

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.     

Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate

1 The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200  mg to 1600  mg were evaluated in healthy subjects.
2 Bismuth was only minimally absorbed (<0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33  ng  ml⁻¹ in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800  mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600  mg.
3 The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose-proportional and consistent with previous observations for ranitidine administered alone.
4 Ranitidine bismuth citrate was well-tolerated in single oral doses of up to 1600  mg.     

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.     

H2-receptor antagonists and antacids have an aggravating effect on Helicobacter pylori gastritis in duodenal ulcer patients

Background : Antacids, such as aluminium–magnesium hydroxide (AlMg(OH)₃), or H₂-receptor antagonists, such as ranitidine, are common drugs used for treating peptic ulcer disease and acid-related symptoms.
Methods : In a prospective double-blind controlled study, 174 patients were randomized to a 4-week course of treatment with either AlMg(OH)₃ (acid-binding capacity: 280 mval/day) or ranitidine 300 mg for active Helicobacter pylori -associated duodenal ulcers (as determined by histology and the urease test). Before and after treatment, two biopsy specimens each were obtained from the antrum and corpus, and the grade and activity of gastritis, as well as H. pylori density, were determined using a score ranging from 0 = none to 4 = severe.
Results : Pre- and post-treatment histology were available for 138 patients (AlMg(OH)₃: 67, ranitidine: 71). Treatment with AlMg(OH)₃ significantly increased the activity of corpus gastritis (Wilcoxon signed-rank: P  = 0.0014), while ranitidine treatment significantly increased both the grade and activity of corpus gastritis ( P  = 0.0002 and P  = 0.0001 respectively). In the antrum, both regimens provoked a significant increase in the frequency of intestinal metaplasia, but this may be a consequence of sampling error.
Conclusions : Ranitidine and AlMg(OH)₃ have an aggravating effect on H. pylori gastritis in duodenal ulcer patients. This should be considered a side-effect of the respective drugs and is more pronounced with ranitidine.