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A very rare case of acetylsulfapyridine nephrolithiasis is presented in a 54-year-old female patient who had been prescribed sulfasalazine (6 x 500 mg/day) because of psoriatic arthritis for the last 9 years. The patient's renal function was only slightly impaired. Reflectance infrared spectroscopy and gas chromatography-mass spectrometry allowed the identification of the chemical nature of the stone. As acetylsulfapyridine is a metabolite of sulfasalazine, administration of the latter drug was the cause of the nephrolithiasis.

During antibiotic treatments, active residuals reaching the colon profoundly affect the bacterial flora resulting in the emergence of resistance. To prevent these effects, we developed an enteric-coated formulated activated-charcoal based product, DAV132, meant to deliver its adsorbent to the ileum and neutralize antibiotic residues in the proximal colon. In a randomized, control, crossover study, the plasma pharmacokinetics of the probe drugs amoxicillin (500 mg) absorbed in the proximal intestine, and sulfapyridine (25 mg) metabolized from sulfasalazine in the cecum and rapidly absorbed, were compared after a single administration in 18 healthy subjects who had received DAV132, uncoated formulated activated charcoal (FAC) or water 16 and 8 hours before, concomitantly with the probe drugs, and 8 hours thereafter. The AUC0-96 h of amoxicillin was reduced by more than 70% when it was taken with FAC, but bioequivalent when it was taken with water or DAV132. By contrast, the AUC0-96 h of sulfapyridine was reduced by more than 90% when administered with either FAC or DAV132 in comparison with water. The results show that DAV132 can selectively adsorb drug compounds in the proximal colon, without interfering with drug absorption in the proximal small intestine, thereby constituting a proof of concept that DAV132 actually functions in humans., (© 2014, The American College of Clinical Pharmacology.)

There was no standard or report for the treatment of rheumatoid arthritis (RA) patients on hemodialysis with Salazosulfapyridine (SASP). We examined the pharmacokinetics of SASP and its metabolites in RA patient on hemodialysis. Hemodialysis was started 2 h after administration of SASP at a dose of 250 or 500 mg. Blood samples were took 8 times during the observation period. The concentration of SASP and its metabolites (SP, Ac-SP) in blood sample were measured. There was no difference for the concentration of SASP before and after hemodialysis. Results showed SASP was nondialyzable, but SP and AC-SP were dialyzable. At a dose of 500 mg, AUC0-∞ of SASP and SP were higher than healthy volunteer. Therapy with SASP for hemodialysis RA should be started at a lower dose for adverse event risk.

Probiotics are live microorganisms claimed to exert beneficial effects on the host. This study investigated their effect on the metabolism and pharmacokinetics of sulfasalazine (SSZ), a drug whose efficacy depends on metabolism by azoreductase (AR) in the gut microbiota to sulfapyridine (SP) and 5-acetylsalicylic acid (5-ASA). The probiotic strains Lactobacillus acidophilus L10, Bifidobacterium lactis B94 and Streptococcus salivarius K12 possessed AR activity and a corresponding ability to metabolize SSZ. Treatment of male Wistar rats (n = 5) with oral 2 g doses of a mixture of the three probiotics (total dose 1.8 × 10⁹ cfu) every 12 h for 3 days resulted in a significant increase (p < 0.05) in AR activity in ex vivo colon contents with a corresponding increase in SSZ metabolism. Similar probiotic treatment of male Wistar rats (n = 8) followed by an oral 100 mg/kg dose of SSZ produced high plasma levels of SP, but pharmacokinetic parameters of SSZ and SP were not significantly different from control rats given SSZ. These results indicate that probiotic strains possess AR activity and can metabolize SSZ. Treatment with probiotics increases AR activity in the gut microbiota but has no effect on plasma levels of SSZ and SP following a subsequent oral dose of SSZ.

Introduction: The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively., Methods: In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15min intravenous infusion of vehicle, atropine (0.06mg/kg) or erythromycin (1mg/kg) followed by an intragastric administration of a mixture of paracetamol (24mg/kg) and sulfasalazine (20mg/kg). Food was given just before or at 6h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT., Results: The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT., Discussion: Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A simple and sensitive liquid chromatography/positive-ion electrospray ionization mass spectrometry (LC-ESI-MS/MS) method has been developed for the simultaneous determination of sulphasalazine (SASP) and its main metabolite sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) with 100 μL of human plasma using dimenhydrinate as the internal standard (I.S.). The API-3000 LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique. Protein precipitation process was used to extract SASP, SP, 5-ASA and I.S. from human plasma. The total run time was 9.0 min and the elution of SASP, SP and 5-ASA was at 4.8 min, 2.5 min and 2.0 min, respectively. The separation was achieved with a mobile phase consisting of 0.2% formic acid, 2 mM ammonium acetate in water (mobile phase A) and 0.2% formic acid, 2 mM ammonium acetate in methanol (mobile phase B) by using gradient elution on a XBP Phenyl column (100 mm × 2.1 mm, 5 μm). The developed method was validated in human plasma with a lower limit of quantitation of 10 ng/mL for SASP, SP and 5-ASA, respectively. A linear response function was established for the range of concentrations 10-10,000 ng/mL (r>0.99) for SASP and 10-1000 ng/mL (r>0.99) for SP and 5-ASA. The intra and inter-day precision values for SASP, SP and 5-ASA met the acceptance as per FDA guidelines. SASP, SP and 5-ASA were stable during stability studies, i.e., long term, auto-sampler and freeze/thaw cycles. The method was successfully applied for the evaluation of pharmacokinetics of SASP, SP and 5-ASA after single oral doses of 250 mg SASP to 10 healthy volunteers., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Aim: To carry out a pilot study to investigate the effect of short-term oral probiotic administration on the metabolism of sulfasalazine (SSZ) in patients with rheumatoid arthritis (RA) stabilized on SSZ., Methods: Twelve subjects with RA taking stable doses of SSZ for a minimum of 3 months prior to the study, received a probiotic preparation contained three strains of bacteria (1.8 x 10(9) CFU/day) twice daily for 1 week. Single point blood and 12-h urine samples were taken before and after probiotic treatment and 3 weeks following discontinuation of probiotics, for determination of SSZ and its metabolites. The presence of the probiotic bacteria in the feces of patients was investigated by denaturing gradient gel electrophoresis (DGGE)., Results: Adverse events recorded were three instances of gastrointestinal disturbance and one flare of RA. Plasma and urinary levels of SSZ and its metabolites showed no statistically significant changes after probiotic administration and the incidence of gastrointestinal disturbance did not appear to be ascribed to higher sulfapyridine plasma levels. Probiotic-specific DGGE bands were detected in the feces of some patients after the treatment period., Conclusions: Short-term treatment of RA patients with a multi-strain probiotic did not significantly influence SSZ metabolism as has been demonstrated in animal models.

Background: Sulfasalazine (SASP) pharmacologic actions are widely applied in clinical therapy. The role of N-Acetyltransferase 2 (NAT2) in the pharmacokinetics of SASP and its metabolites has not been clarified. We investigated the effects of genetic polymorphism of NAT2 on pharmacokinetic profiles of SASP and its two metabolites, sulfapyridine (SP) and N-acetylsufapyridine (AcSP)., Methods: Eighteen subjects were recruited and divided into 3 groups by NAT2 genotype: wild type (w/w), heterozygous variant (w/m), homozygous variant (m/m). After taking 1000mg SASP tablets, the plasma concentrations of SASP, SP and AcSP were measured with HPLC method and pharmacokinetic parameters were calculated by using the computing program 3P97., Results: The AUC(0)(-)(72) and Cmax of SP in m/m subjects were significantly higher than those in w/m and w/w subjects, with the values of 172.57+/-49.42, 103.38+/-39.85, 71.37+/-17.52mg h/l, and 9.65+/-2.34, 6.10+/-1.79, 4.55+/-1.38mg/l, respectively. In contrast, the AUC(0)(-)(72) of AcSP was significantly lower in m/m subjects. The Cmax of AcSP in w/w, w/m and m/m subjects was 12.67+/-3.32, 9.07+/-2.29 and 4.22+/-0.93mg/l, respectively, with significant differences among groups. However, there was no significant difference in any pharmacokinetic parameter of SASP among groups., Conclusion: Different NAT2 genotypes, leading to functional heterogeneity of NAT2, may affect pharmacokinetics of SP and AcSP. Therefore, genotyping NAT2 gene before administration would be important in SASP therapy.

Background: Sulphasalazine is used for the long-term maintenance therapy of ulcerative colitis to prevent the relapse of symptoms. However, its clinical use is often restricted by its serious adverse effects., Objective: Leucopenia occurred in a patient with severe renal dysfunction after administration of sulphasalazine. The present study was designed to examine whether the adverse event was associated with a disability in the metabolism of sulphasalazine., Subject: A 29-year-old male patient with ulcerative colitis, who underwent haemodialysis thrice a week because of severe renal dysfunction. The chief complaint was diarrhoea., Methods: Serum concentrations of three major metabolites of sulphasalazine, (5-aminosalicylic acid, sulphapyridine and N-acetyl-sulphapyridine), were measured. The polymorphism of N-acetyltransferase 2, an enzyme that metabolizes sulphapyridine, was also determined by polymerase chain reaction., Results: The trough levels of 5-aminosalicylic acid, sulphapyridine and N-acetyl-sulphapyridine were 0.77-1.45 microg/mL, 31.20-39.25 microg/mL and 14.19-15.03 microg/mL, respectively. The gene diagnosis of N-acetyltransferase 2 suggested that the type was classified as NAT2*6A/*7B, indicating that the patient was a slow acetylator., Conclusion: The patient was a slow acetylator, which might lead to a rise in the serum sulphapyridine concentration. Moreover, the decrease in protein binding of sulphasalazine as a result of severe renal dysfunction might have potentiated the effect because of the extremely high protein binding of this compound. Thus, it is most likely that these two factors contributed to the sulphasalazine-induced leucopenia.

Objective: A high-performance liquid chromatography (HPLC) with an automated on-line column-switching system was used for the simultaneous determination of sulphapyridine and acetylsulphapyridine, two major active metabolites related to the adverse effects of sulphasalazine, in human serum., Methods: Serum samples were directly injected into the HPLC, with the valve automatically switched on to remove serum proteins and other hydrophilic components remaining in the pre-column after elution of sulphapyridine and acetylsulphapyridine to the analytical column., Results: Serum proteins did not interfere with the analysis of either compound. The recoveries of SLP and Ac-SLP from drug-free human serum were 93.03-99.18% and CV were 2.88-4.34%. The within-run reproducibility of assays was excellent with relative standard deviations (RSD) of 1.01-3.90% (SLP) and 0.77-5.56% (Ac-SLP). The limit of quantification of sulphapyridine and acetylsulphapyridine was 3.13 microg/mL and 0.50 microg/mL, respectively. The serum concentrations in a patient with ulcerative colitis, who took 1.0 g sulphasalazine twice daily, were 31.20 microg/mL for sulphapyridine and 14.64 microg/mL for acetylsulphapyridine at 7 h after ingestion., Conclusion: The present simple and reproducible assay was useful for the monitoring of serum sulphapyridine and acetylsulphapyridine.

Sulfapyridine (SP), one of the metabolites of sulfasalazine (SASP), is further metabolized into N-acetylsulfapyridine (AcSP) by polymorphic N-acetyltransferase 2 (NAT2). NAT2 activity has been diagnosed by phenotyping, that is, evaluating plasma concentrations or urinary excretions of tentatively administered test drugs for dose individualization and avoidance of serious adverse events. Herein, we investigated the relationship between NAT2 genotypes and the pharmacokinetics of SP in healthy Japanese subjects, as well as the adverse events of SASP in patients with inflammatory bowel disease (IBD). Eight healthy subjects and 13 IBD patients were classified into three groups by NAT2 genotyping; the homozygote for the wild-type allele (Rapid Types), the compound heterozygote for the wild-type and mutant alleles (Intermediate Types), and the homozygote for mutant alleles (Slow Types). A single oral dose of 40 mg/kg SASP was administered to each healthy subject, and plasma and urine samples were taken until 51 and 72 h after administration, respectively. Both the SP and AcSP concentrations in each sample were determined by the HPLC method. The NAT2 genotypes were well-correlated with the plasma concentrations or urinary excretions of SP and AcSP in 8 healthy subjects, except for one Slow Type. In patients with IBD, skin rash was seen in 3 of 6 Rapid Types and 1 of 6 Intermediate Types, consistent with the concept that hypersensitive reactions are independent of serum SP concentrations. In contrast, SASP dosing-related acute pancreatitis was found in the Slow Type patient. In this case, the NAT2 activity was diagnosed by genotyping in advance, and the medical staff could pay scrupulous attention, resulting in no serious subjective symptoms such as abdominal pain, anorexia or fever. Further investigations on the relationship between the NAT2 genotype and adverse events are required, although genotyping appeared to be a promising method to avoid such serious adverse events.

The spontaneous behaviour and the apparent digestibility of dry matter and fibre and transit times of digesta were compared in four normal horses and four crib-biters. A technique was developed for measuring total gut transit times (TGTT) by using single-stool analysis of the passage of radio-opaque polyethylene markers. Longer TGTT were recorded in the crib-biters than in the normal horses but the orocaecal transit times did not differ. The crib-biters rested less than the normal horses.

Aims: Lanreotide is a novel synthetic somatostatin analogue. A long-acting formulation of lanreotide has been shown to be effective for the treatment of gastroentero-pancreatic hormone-producing tumours but effects on postprandial digestive and absorptive functions remain obscure. The aim of the present study was to evaluate the effects of intravenous lanreotide on gastric and biliopancreatic secretions in man as well as the absorption of nutrients and the duodeno-caecal transit time after ingestion of an homogenized meal (500 kcal, 55% carbohydrates, 15% proteins, 30% lipids)., Methods: Eight healthy male volunteers were studied on two occasions within a 2 weeks interval, using a perfusion method. They received in single-blind and random order continuous i.v. infusion of either placebo or lanreotide (100 micrograms h-t after a bolus of 100 micrograms 15 min before the beginning of the study)., Results: Lanreotide significantly decreased gastric acid secretion (90%) for the initial 3 h period. Gastric emptying was not significantly modified by lanreotide infusion. Compared with placebo, lanreotide almost completely abolished both bile salts and lipase responses to the meal. It largely increased the duodeno-caecal transit time and decreased significantly the duodenal absorption of carbohydrates and triglycerides., Conclusions: Since lanreotide has powerful effects on gastrointestinal functions, it could be useful in the prevention or in the treatment of pancreatic and bowel fistulas as well as short bowel syndrome.

A peroral dosage form was examined to deliver recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the colon in beagle dogs. A new gelatin capsule with its inside surface coated with ethylcellulose was prepared for this purpose. RhG-CSF was dissolved with propylene glycol and was filled in the capsule. Several kinds of ethylcellulose-gelatin capsules with an ethylcellulose layer of thickness 46 to 221 mm were used. The capsule was filled with propylene glycol solution containing fluorescein as an absorption marker, castor oil derivative and citric acid. The hardness of the capsule was tested after the gelatin layer was dissolved using a hardness tester and was dependent on the thickness of the ethylcellulose layer of the capsule. The time, Tmax, at which plasma fluorescein level reaches its maximum following oral administration of ethylcellulose capsules was used as a parameter for the in-vivo disintegration time of the ethylcellulose capsule into the colon. Capsules of thickness 84 mm with a Tmax of 4-6 h were filled with rhG-CSF solution containing fluorescein and were administered to dogs. After administration, blood samples were collected for 96 h and the blood total leucocyte (BTL) counts were measured as a pharmacological index of rhG-CSF. The maximum BTL count appeared at 10 h then gradually decreased and returned to its normal level at 48 h. These results suggest the usefulness of ethylcellulose capsules for the delivery of rhG-CSF to the colon and the possibility of a new oral rhG-CSF dosage form has been elucidated.

Orocaecal transit time (OCTT) was assessed in six healthy beagles by means of the breath hydrogen test (BH2T) and the sulphasalazine/sulphapyridine method (SLZ) after the administration of a test meal of canned food mixed with sulphasalazine. Orocaecal transit time was defined as the time taken from the oral administration of the test meal to the time when the first portion of the meal reached the colon. In five of the dogs the OCTTs assessed by the BH2T were shorter than those measured by the SLZ method by 30, 15, 45, 30 and 45 minutes. However, the median OCTT assessed by the BH2T (135 minutes, range 120 to 195 minutes) was not significantly different from that measured by the SLZ (180 minutes, range 150 to 210 minutes) and was highly correlated with it (r = 0.94, P = 0.016). The sixth dog maintained baseline hydrogen and plasma sulphapyridine readings throughout the monitoring period and the OCTT could not be measured.

Purpose: We propose a noninvasive method for the measurement of orocecal transit time assessed by the sulfapyridine appearance time in saliva after ingestion of sulfasalazine., Method: In 12 healthy volunteers, we studied the correlation between plasma and saliva sulfapyridine appearance times and then the sulfapyridine appearance times in saliva under various experimental conditions to assess the reproducibility, the effects of meals, and the role of the formulation, and the effects of gastrointestinal kinetic drugs., Results: The correlation between saliva and plasma sulfapyridine appearance times was strong (r = 0.84; p = 0.0004). The sulfapyridine saliva appearance time was significantly delayed by the meal. Compared with placebo, the saliva sulfapyridine appearance time was reduced by cisapride (312 +/- 128 versus 551 +/- 97 minutes; p = 0.0001) and increased by loperamide (674 +/- 267 versus 501 +/- 131 minutes; p = 0.044)., Conclusion: We propose the salivary sample method as a validated simplification of the plasma sulfasalazine-sulfapyridine test for the measurement of orocecal transit time.

The effects of zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebo-controlled study enrolling 14 healthy male volunteers. All subjects received SASP 1 g every 12 hours for 8 days and zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.

The interaction between sulphasalazine and cimetidine has been studied, a drug combination which is quite likely in view of the higher incidence of peptic ulceration in patients with RA. Nine patients with RA on sulphasalazine (group I) were given cimetidine 400 mg three times daily and followed up for 18 weeks. In addition, five patients on sulphasalazine alone (group II), who served as a control group, were also followed up in the same manner as group I. Monitoring included assessment of disease activity and haematological variables, and measurement of plasma and urinary levels of sulphapyridine and its metabolites. There was no significant change in either the haematological parameters or sulphapyridine pharmacokinetics upon administration of cimetidine. We therefore conclude that cimetidine may be safely used in patients with RA who are being treated with sulphasalazine.

The pharmacokinetic disposition of sulfasalazine and its metabolites was studied in 8 young and 12 elderly patients with active rheumatoid arthritis. Equal numbers of slow and fast acetylators were included in each age group. Patients received enteric-coated sulfasalazine 2g daily for 21 days; specimens of serum and urine were collected for 96 h after administration on days 1 and 21. The elimination half-life of sulfasalazine was greater in the elderly patients. Many disposition parameters of sulfapyridine differed in slow and fast acetylators; of greatest significance were the increased values of steady-state serum concentration in the slow acetylators. There was no effect of age on any sulfapyridine disposition parameters. Values for the steady-state serum concentrations of N-acetyl-5-acetylsalicylic acid were greater in elderly than in young patients. The metabolism of sulfapyridine was markedly affected by acetylator phenotype and this was reflected in the composition of sulfapyridine-related material in the urine. Thus, age is a determinant of the steady-state concentrations of salicylate moieties but acetylator phenotype plays a greater role in determining the serum concentration of sulfapyridine, which has greater therapeutic implications in rheumatology.

Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.

The relationship between the oral absorption and gastrointestinal transit time of nitrofurantoin was investigated in dogs by the double-marker method using acetaminophen and salicylazosulfapyridine as markers. The extent of bioavailability of nitrofurantoin gave correlations with both gastric emptying time and small intestinal transit time. The results indicate that the slower the passage from the stomach into the small intestine and/or the longer the residence time in the small intestine, the oral absorption efficiency of nitrofurantoin increases. These observations were consistent with the reported findings from in situ absorption study in rats and intestinal intubation study in humans, respectively. Moreover, it was clarified that small intestinal transit time is the most important determinant of absorption of nitrofurantoin, since the good correlation was observed between the small intestinal transit time and the extent of bioavailability. The double-marker method appears consequently to be useful tool for the determination of the gastrointestinal transit time in dogs.

The inter- and intrasubject variability of the orocecal transit time assessed by the salicylazosulphapyridine/sulphapyridine test was examined. Nine healthy males attended on 3 occasions. Between-days comparison gives highly reproducible transit times for the subjects considered as a group (median values and their 95%-confidence limits): 4.0 (3.5-4.5), 4.5 (3.5-5.0), and 4.5 (3.0-4.5) hours, respectively. Fifty-nine per cent of the individual transit times amounts to 4.0 or 4.5 hours. Within subject comparison revealed marked differences for 4 of the volunteers. The maximum between-days differences observed were 1.0 (3 subjects) and 2.5 hours, respectively. Similar results of variability become evident regarding the area under the sulphapyridine concentration-time curves. In conclusion, it appears reasonable to use this method in assessing e.g. the effects of drugs on the transit time in crossover studies.

An HPLC method is described for the simultaneous and rapid determination of sulfasalazine (salicylazosulfapyridine) and two of its metabolites, sulfapyridine and N-acetylsulfapyridine, in human serum. The range of quantitation is 0.1 to 12 micrograms/mL for sulfasalazine and sulfapyridine and 0.25 to 12 micrograms/mL for N-acetylsulfapyridine. Serum is mixed with acetonitrile containing the internal standard sulfamethazine and the ion-pairing agent tetraethylammonium chloride. The acetonitrile extract is concentrated and analyzed by HPLC, using a new polymer-based column, and detected by UV spectroscopy at 270 nm. This paper is the first both to describe the simultaneous analysis of all three of the compounds from serum and to present sulfasalazine concentration-time data following oral administration to humans.

The pharmacokinetics of sulphasalazine and its principal metabolites in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) were compared. Patients with RA had a significantly greater concentration of plasma sulphapyridine than patients with IBD (medians 14.0 micrograms/ml and 7.4 micrograms/ml respectively). Patients with RA also tended to maintain a higher plasma sulphapyridine concentration with time, as determined by the area under the curve (AUC), but a lower plasma sulphasalazine AUC than patients with IBD. It is suggested that more sulphasalazine may be presented to the lower bowel for cleavage to sulphapyridine and 5-aminosalicylic acid in patients with RA than in IBD. Patients with RA may also have impaired metabolism of sulphapyridine as a consequence of their disease. Together these factors may contribute to higher peak circulating sulphapyridine concentrations and may be responsible for the higher incidence of side effects of sulphasalazine treatment in patients with RA than in patients with IBD.

We examined 122 patients with inflammatory bowel disease treated with salicylazosulfapyridine. Forty-two (34.5%) had adverse effects that led to discontinuation of therapy in 14 (11.5%). In 33 patients the effects appeared to be dose dependent. The plasma sulfapyridine levels in patients exhibiting gastrointestinal side effects were significantly higher than in patients with no adverse effects (41.0 +/- 20.3 and 23.8 +/- 14.8 micrograms/ml respectively, P less than 0.001). Plasma sulfapyridine levels were significantly higher in slow than in fast acetylators (31.5 +/- 17.1 vs. 22.2 +/- 17.1 micrograms/ml). Slow acetylators had three times as many side effects as fast acetylators; however this difference was not statistically significant.

A high-pressure liquid chromatographic method for the sensitive, rapid, and specific determination of sulfapyridine and its N-acetyl derivative in plasma and saliva was developed. A cyano-bonded, reversed-phase, high efficiency column was used. The system detected these sulfonamides in serum to 0.25 mg/liter and within only 6 min. Sulfapyridine was separated from its acetyl derivative with little interference from other drugs. The assay reproducibility was within 3%. The assay was highly useful for routine monitoring of patients receiving sulfasalazine for inflammatory bowel disease.

For determination of the sulphapyridine level there were used 83 sera of 57 patients with Crohn's disease or ulcerative colitis which were treated with salazosulphapyridine. In 22,8 percent there was a sulphapyridine level higher than the therapeutic range of the whole sulphapyridine of 20-50 micrograms/ml. The serum levels are below this range frequently. Sulphonamide containing drugs yield too high values. Generally no sulphapyridine is shown in the serum because of the missing splitting of the salazosulphapyridine in patients with colectomie. Low serum values are found at low patient-compliance. In diarrhoea sulphapyridine levels in the serum are decreased. Determination of the sulphapyridine level is suitable: a) for recognition of too high serum levels and therefore for prevention of side effects b) to make sure that the therapeutic range is reached.

Fifteen children followed as outpatients with chronic inflammatory disease of the colon were given sulfasalazine in doses from 1 to 4 gm/day (22 to 68 mg/kg, or 0.69 to 2.33 gm/m2). No correlation was found between the dose/m2 administered and the total serum sulfapyridine levels. However, 11 of 15 patients achieved SP levels greater than or equal to 17 micrograms/ml, a level approximating that reputedly associated with therapeutic efficacy. Patients who were either slow acetylators or slow hydroxylators of sulfapyridine had total SP levels significantly higher than patients who were both rapid acetylators and hydroxylators (20.0 +/- 1.2 vs 14.6 +/- 1.6). Total SP serum levels were not correlated with the activity of the disease. No toxic levels (greater than 50 micrograms/ml of SP) were encountered. We conclude that a dose of SASP in the range of 1.5 to 2.0 gm/m2 can be safely administered to children and is usually associated with serum SP levels considered in the therapeutic range. Although one-third of children are both rapid acetylators and hydroxylators and will have somewhat lower SP levels, the routine monitoring of SASP therapy with SP levels is not necessary for management of disease.

One hundred and eighty-five patients with ulcerative colitis have been studied serially while receiving regular maintenance treatment with sulphasalazine (SASP) in a dose of 0.5 g four times daily. The circulating levels of the drug and its principal metabolites during remission do not influence the liability to relapse. When relapse does occur, the circulating level of sulphapyridine falls and remains depressed until remission occurs. This fall during a relapse is most pronounced when the patient suffers from universal colitis and is least marked in cases of distal colitis.

The time course of free and N4-acetylated sulfapyridine (SP) concentrations in the saliva and whole plasma was determined in a healthy male volunteer after a single 2.0 g oral dose of salicylazosulfapyridine (SASP) as four-500 mg commercial, uncoated tablets. The mean (+/- S.D.) plasma: saliva concentration ratios for free and acetylated SP was 2.04 (+/- 0.24) and 3.12 (+/-0.43), respectively, and were independent of plasma concentration and saliva pH. The elimination half-lives of SP and N4-acetyl SP could be determined from either salivary or plasma concentration-time data. These preliminary results suggest that measurement of saliva concentrations of free and acetylated SP may be a convenient, noninvasive method for monitoring indirectly the plasma concentrations of SP and acetyl SP in patients treated with SASP and for determining acetylator phenotype.

Previous studies of sulphasalazine in rheumatoid arthritis have chosen an empirical dose based upon its use in ulcerative colitis. In this study we compare the efficacy and toxicity of two doses (1.5 g/day and 3 g/day, 30 patients per group), and attempt to relate efficacy to serum levels of sulphasalazine and its metabolites. After six months 24 of the low-dose group and 20 of the high-dose group remained on treatment. Greater improvement was seen in the high-dose group. When dose was expressed as mg/kg, the dose efficacy ratio became more apparent and a dose of greater than 40 mg/kg/day appears to confer greater benefit. No relationship was demonstrated between serum levels of sulphasalazine or its measured metabolites, and efficacy. We conclude that response to sulphasalazine in rheumatoid arthritis is dose dependent but does not relate to serum levels of sulphasalazine, sulphapyridine, or acetyl sulphapyridine.

Twelve pregnant patients with ulcerative colitis or Crohn's disease who were being treated with sulphasalazine (SASP) were studied together with their newborn, full-term babies. An earlier study had shown almost identical concentrations of SASP and its metabolic sulphapyridine (SP) in maternal and cord serum. As controls, blood samples were collected from 25 healthy women and their newborn infants. Sera from mothers and infants were analysed for the vacant amount of high-affinity bilirubin binding site on albumin (reserve albumin) by the MADDS method. The mean reserve albumin concentration of the SASP-treated mothers was 9% lower than that of the controls, which is probably insignificant. No difference was observed in the corresponding two groups of infants. In vitro studies showed that neither SASP nor SP in therapeutic plasma concentrations had a significant bilirubin-displacing capacity. It seems that SASP preferentially is bound to other sites on albumin than to the high-affinity binding site for bilirubin. The risk of kernicterus in the full-term newborn does not seem to be increased by treatment of the mother with sulphasalazine.

Estimations of the serum level of sulfapyridine in 21 patients suffering from colitis ulcerosa or Crohn's disease, have been carried out. Nearly 50 per cent of all the serum levels were within the therapeutic range between 20 and 50 micrograms/ml. Some factors influencing the sulfasalazine metabolism are mentioned. The estimation of the serum levels of sulfapyridine is a suitable method for supervision of patients receiving treatment with sulfasalazine.

The present study was undertaken to determine if bran added to a fiber-free diet (milk) would modify the absorption of orally administered chloramphenicol (cmp) compared with that observed on a standard concentrates diet in pig. The plasma chloramphenicol level was maximal (0.47 +/- 0.26 microgram/mL), 3.5 h after a meal of concentrates containing 8 g of chloramphenicol palmitate; this highest concentration represented only 30% of that observed 12 h after a meal of substituted milk and 14% of the maximal plasma concentration of chloramphenicol detected 14 h after a milk meal when supplemented with bran (100 g). Over 24 h, the plasma availability of chloramphenicol with the three tested diets represented, respectively, 11.4% (concentrates), 17.2% (milk), and 74.1% (milk + bran) of that obtained for intravenous administration; similar oral--caecal transit times were observed for these three diets. It was concluded that the presence of bran in the regimen strongly increases the intestinal absorption of chloramphenicol palmitate, with the lowest rate of absorption on standard concentrates, and it is tempting to speculate that this increase is due to a more rapid intestinal hydrolysis by an increased pancreatic lipase activity on bran.

Salicylazosulfapyridine (SASP) is a drug used in the treatment of ulcerative colitis (UC) owing to the therapeutic action of the 5-aminosalicylic acid produced by the splitting of the molecule in the cecum, which also yields the absorbable compound Sulphapyridine (SP). The aim of our work was to assess the levels of the drug in blood (SASP and SP), to correlate them with undesirable effects in any, to verify their fluctuations in the dosing interval and to investigate the extent of the excretion of the drug in the children who were studied. 10 children (6 to 16 years) with UC, who were treated with SASP (dOsage schedule 0.5-2.0 g/day in a 12 hours interval), were studied. Blood levels of SASP and SP were assessed at 6 and 12 hours after doses, and total fecal excretion of SASP was determines in 24 hs specimens. All the determinations were performed according to Hansson and Sandberg. SP plasma levels were 17.7 +/- 9.0 ug/ml (range 6.8-36.3 ug/ml) at 6 hours after doses. and 14.1 +/- 7.2 ug/ml (range 5.7-25.0 ug/ml) at 12 hours after doses. SASP plasma levels were 15.5 +/- 15.4 ug/ml (range 2.1-53.4 ug/ml) at 6 hours after doses, and 14.0 +/- 20.4 ug/ml (range 3.9-70.7 ug/ml) at 12 hours after doses. The 24 hours fecal excretion was 17.4 to 236 mg. These values were correlated with the given doses (r = 0.88) calculated as SASP g/m2 body surface 24 hs. There was no statistical correlation between doses and SP or SASP levels in this group, and the respective levels of SASP and SP at 6 and 12 hours after doses showed no significative differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventeen patients with ulcerative colitis and three patients with Crohn's disease exhibited different side effects during sulfasalazine therapy. Eighty percent of these patients belonged to slow acetylator phenotypes. All side effects except skin rash were associated with a mean serum total sulfapyridine concentration of 62.9 +/- 17.4 micrograms/ml and free sulfapyridine concentration of 42 +/- 9.5 micrograms/ml. All patients were successfully desensitized, which allowed them the benefit of continued sulfasalazine therapy for prevention of relapses.

The effect of ethanol of blood levels of free and conjugated sulfonamides (sulfanilamide and sulfapyridin) and isoniazid was investigated in mice. Ethanol (1.5 and 4 mg/g i.v.) enhanced the amount of conjugated isoniazid without affecting the total amount of isoniazid in blood, and tended to raise the total amount of the sulfonamides.

Serum concentrations of sulphasalazine and sulphapyridine were measured during the first week of life in 15 children whose mothers had been on sulphasalazine during pregnancy. The serum concentrations of sulphapyridine and sulphasalazine were similar in the children and their mothers at delivery. The elimination rate of the drugs in the newborn children was slow but the concentrations were not so high that a bilirubin displacing effect could be expected. In eight mothers who were breast-feeding and taking sulphasalazine, analyses were done of mothers' serum, breast-milk and serum from their children. The results showed that the amount of sulphasalazine and sulphapyridine transferred to the child via the breast-milk is negligible with regard to the risk of kernicterus. It is concluded that a woman in need of sulphasalazine treatment can continue the medication throughout pregnancy and lactation without risk of development of kernicterus in her child. Only term infants without haemolytic disease were included in the study. Thus our conclusion is not necessarily valid for the prematurely born child or the child with haemolytic disease.

The appearance of sulfapyridine in plasma after oral administration of salicylazosulfapyridine (SASP) was evaluated as a method for defining arrival time in the cecum, an index of small bowel transit. After direct instillation of SASP and lactulose into the cecum, the appearances of their metabolites (sulfapyridine in plasma and hydrogen in breath) were rapid (1-10 min) and simultaneous. When a mixture of SASP and lactulose was taken by mouth, times of the respective "signals" varied among individuals from 40 to 180 min (n = 8) but were correlated within individuals. Salicylazosulfapyridine transit times from duodenum to cecum were also very similar to simultaneous measurements of transit by scintigraphic monitoring of technetium 99m. Timing of the sulfapyridine signal corresponded to the arrival of 5%-13% of technetium 99m DTPA in the cecum. Exemplifying the use of this new technique, simultaneous administration of lactulose into the stomach and SASP into the duodenum yielded consistently longer stomach-to-cecum than duodenum-to-cecum transits, attributable to the delay caused by gastric emptying. Therapeutic doses of morphine delayed small bowel transit of SASP. Transit of SASP offers a second marker technique for the cecal arrival of the "head" of a bolus; the approach may be useful as an inexpensive, noninvasive measurement of transit.

The steady-state concentrations of sulphasalazine and sulphapyridine in serum and mother's milk have been measured in 12 nursing patients who were being treated with sulphasalazine. The results show that sulphasalazine passes only in negligible amounts or not at all into milk. The concentration of sulphapyridine in milk was about 40% of the serum concentration in the mother. We therefore conclude that sulphasalazine may safely be given during nursing.