Fi Rst Dose Research Articles

Antidiarrheal Activity Test of White Pomegranate (Punica granatum L.) Infusion on Swiss Webster Male with Oleum Ricini Method

Diarrhea is a condition in which a person defecates with a soft or liquid consistency, which can evenbe water. Diarrhea can be treated with drugs derived from plants, one of which is white pomegranate skin. Theskin of white pomegranate (Punica granatum L.) is thought to have anti-diarrheal activity because it has fl avonoidsand tannins. This study aims to determine the activity and optimal dose of pomegranate skin infusion.Mice were grouped into 5 groups: negative control (Na CMC 0.5%), positive control (Loperamid HCl), andpomegranate peel infusion test group with a dose of 8 mg / 20 g mice BW, 16 mg / 20 g weight mice and 32 mg./ 20 gr BB mouse. Mice induced diarrhea with Oleum ricini, 30 minutes later the mice were given a test preparation.The onset of diarrhea, stool consistency, diarrhea frequency, duration of diarrhea and stool weight weremeasured every 30 minutes for 6 hours. The results showed that the fi rst dose (8 mg / 20 gr BW of mice) wasthe optimal dose for the initial parameters of diarrhea and fecal weight, which means that there was a signifi cantdiff erence with negative control and positive control (<0.05). The parameters of stool consistency, frequency ofdiarrhea and duration of occurrence of diarrhea showed no signifi cant diff erence between groups of 8 mg / 20 gmice BW, 16 mg / 20 g mice BW and 32 mg / 20 g mice BW, negative control and positive control (p> 0, 05).

The effects of caffeine on drowsiness in patients with narcolepsy: a double-blind randomized controlled pilot study.

The effects of caffeine on drowsiness and reaction time in patients with narcolepsy are unclear. We aimed to assess the effects of caffeine as add-on therapy in narcolepsy patients. A randomized, double-blind, placebo-control clinical pilot trial was conducted with a parallel, two-arm trial allocation ratio of 1:1. Participants attended two study visits 7days apart. The drug was administered orally in a single opaque capsule containing 200mg caffeine/placebo daily in the morning for 1week. Sleepiness was assessed objectively using infrared reflectance oculography to measure the percentage of long eye closure (LEC%) and subjectively using two sleepiness scales, the Stanford Sleepiness Scale (SSS) and Karolinska Sleepiness Scale (KSS). Parameters were measured at baseline (BL) prior to taking the drug, after taking the first dose (FD), and after 1week (WD) of daily caffeine. Sixteen participants with narcolepsy were included. No significant differences between groups in baseline measurements were observed. LEC% was significantly decreased after the FD and WD compared with baseline levels (BL 1.4 ± 2.1 vs. FD 0.06 ± 0.0.6 and WD 0.03 ± 0.04). Significant improvements in alertness were observed using the KSS when comparing BL with FD and WD (6.3 ± 1.6, 4.9 ± 1.7, and 4.7 ± 1.7, respectively; p = 0.01). No changes in reaction time or SSS scores were noted. Our findings suggest that a small dose of caffeine has positive effects on alertness in patients with narcolepsy. However, larger trials are required to confirm these findings. ClinicalTrial.gov NCT02832336.

İlk Doz Bupropion HCL Sonrası Edinsel Uzun QT Sendromu ve Jeneralize Tonik Klonik Nöbet

Uzun QT sendromu, doğumsal veya sonradan kazanılmış formları olan ve ölümcül ritm bozukluklarına sebep olabilen bir patolojidir. Doğumsal tip uzun QT sendromunun membran iyon kanallarındaki yapısal ve fonksiyonel bozukluklardan kaynaklanabileceği düşünülmektedir. Diğer taraftan ilaçlar, elektrolit bozuklukları, bazı toksinler, miyokart iskemisi, ileti anormallikleri ve hipotiroidi gibi endokrin bozukluklar ise sonradan kazanılmış uzun QT sendromunun günümüzde bilinen nedenleri arasında yer almaktadır. Gerek antidepresan olarak, gerekse sigara bağımlılığı tedavisinde yoksunluk semptomlarının giderilmesinde kullanılan bupropion, QT uzaması yapabilen ilaçlardandır. Ancak, bupropionun 1.5 g/gün altında kullanımına bağlı QT uzaması oldukça nadir görülen bir durumdur. Bu yazıda, ilk doz 600 mg yavaş salınımlı bupropion alımı sonrasında ortaya çıkan jeneralize tonik klonik nöbet ve geçici QT uzaması yaşayan 26 yaşındaki kadın hasta sunulmaktadır.

Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects

Mifepristone is approved to control hyperglycemia in adults with endogenous Cushing's syndrome and is described as a mildly QTc prolonging drug, based on a TQT study. The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasma mifepristone concentrations exceeding those observed in the TQT study. Twenty healthy, male volunteers were given three doses of 1200 mg mifepristone every 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study. Holter ECG recordings were made on Day 1 and 2. Eighteen subjects completed the study. Mean peak plasma mifepristone concentrations were 4.01 μg/mL (CV: 31%) on the fi rst dose and 5.77 μg/mL (CV: 29%) on the third dose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from- -baseline QTcF (ΔΔQTcF) was between -1.6 and 0.7 ms on the fi rst dose (upper bound of 90% CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms). Concentration effect modeling showed a slightly negative slope of -0.01 ms/ng/mL. Mifepristone did not cause a clinically meaningful QTc prolongation in healthy volunteers at plasma concent rations of mifepristone and its main metabolites that clearly exceeded those seen in a previous TQT study.

Histological Observation Related to the Use of Laser and Ultrasound on Bone Fracture Healing

Objective: To study the effect of both laser and ultrasound radiation on bone fracture healing process. Materials and Methods: Nd:YAG laser (1064 nm wavelength, 135 mW power, 16 joules energy) and ultrasound (1 MHz frequency, 50 mW/cm2 power intensity) were used in this work. Fifteen mature, male, albino rats, were divided into three groups and subjected to a partial fracture on the lateral aspect of femur by a sharp blade. The fi rst group of these animals served as control group. The second group was illuminated by the Nd:YAG laser for two minutes; the fi rst dose was given immediately after surgical fracture induction; the other doses were given on days two, three, six and then one dose weekly for the next three weeks while the third group were treated by the addition of the CW ultrasound perpendicular to the laser treatment in the second group. Results: The present study showed that ultrasound increases the penetration of laser power through the tissue. The histological assessments at day 28 after the fracture of fi rst group showed incomplete healing of the bone with disfi guration and disarrangement of Haversian system and the periosteum was not yet well developed. Treatment with laser showed irregularity and lack of Haversian system formation in bone healing of the second group. The laser and ultrasound treated group (third group) expressed a complete healing at the site of fracture with a complete layer of periosteum and a well arranged Haversian system. Conclusion: Combination of laser and ultrasound in therapy can enhance healing process of a fractured bone more than laser therapy alone, as ultrasound increases the depth of laser penetration in tissue.

New drugs: Methylnaltrexone bromide, alvimopan, and rilonacept

Agent for opioid-induced constipation Each year, an estimated 1.5 million Americans are treated with an opioid analgesic (e.g., morphine) on a continuous basis to relieve pain associated with incurable cancers, end-stage chronic obstructive pulmonary disease from emphysema, heart failure, and other advanced illnesses. The analgesic benefi ts of the opioids result from their action at receptors in the central nervous system (CNS). However, the opioids also act at opioid receptors in peripheral tissues such as the gastrointestinal tract, one of the consequences of which is that almost all patients who are treated with these analgesics on a continuous basis will experience constipation. To reduce the likelihood of constipation, the use of a bowel regimen (i.e., a laxative such as senna [e.g., Senokot] and a stool softener such as docusate [e.g., Colace]) is usually recommended for patients who are to be treated with an opioid analgesic on a continuous basis. For many patients, however, even the use of a bowel regimen is insuffi cient to prevent opioid-induced constipation, and patients experience symptoms and discomfort that add to those associated with the underlying disease. Methylnaltrexone bromide (Relistor—Progenics; Wyeth) is an opioid antagonist that is related to naltrexone (e.g., ReVia, Vivitrol) that has been used for treating opioid and alcohol dependence. The new drug is a quaternary amine that does not cross the blood– brain barrier, and it functions as a selective peripherally acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract. Therefore, it decreases the constipating action of opioid analgesics without reducing the centrally mediated analgesic effects. Methylnaltrexone is administered subcutaneously and is indicated for treating opioid-induced constipation in patients with advanced illness who are receiving palliative care, when the response to laxative therapy has not been suffi cient. Its unique mechanism of action provides a very useful alternative for patients in whom conventional laxatives have not been effective in preventing or treating constipation associated with the use of opioids. The effectiveness of methylnaltrexone was demonstrated in placebo-controlled studies. In a single-dose study, approximately 60% of the patients treated with the new drug experienced a laxative action within 4 hours following administration of the drug compared with 14% of those receiving placebo. In a study in which methylnaltrexone was administered every other day, those receiving the drug had a higher rate of laxation within 4 hours of the fi rst dose (48%) than placebo-treated patients (16%). Methylnaltrexonetreated patients also had signifi cantly higher rates of laxation within 4 hours after at least two of the fi rst four doses (52%) compared with placebo-treated patients (9%). In both studies, approximately one-third of the patients reported laxation within 30 minutes following administration of the drug. The use of methylnaltrexone in an orally administered formulation for treating opioid-induced constipation is currently being evaluated, as is an intravenously administered formulation in the treatment of postoperative ileus. The adverse events reported most frequently with the use of methylnaltrexone include abdominal pain (29%), fl atulence (13%), nausea (12%), dizziness (7%), and diarrhea (6%). If severe or persistent diarrhea occurs during treatment, the drug should be discontinued. There is no known risk of dependency with methylnaltrexone, and it is not a controlled substance. The use of the new agent is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If a patient stops taking the opioid analgesic, the use of methylnaltrexone should also be discontinued. Methylnaltrexone is classifi ed in Pregnancy Category B and should be used during pregnancy only if the anticipated benefi t outweighs the risk to the fetus. Its effectiveness and safety in pediatric patients have not been evaluated. Following administration of methylnaltrexone, peak concentrations are usually achieved within 0.5 hour. It undergoes only limited metabolism, and approximately 85% of a dose is eliminated as unchanged drug. Approximately one-half of a dose is excreted in the urine and somewhat less in the feces. The dosage should be reduced in patients with severe renal impairment, but dosage adjustment is not necessary in patients with mild or moderate renal or hepatic impairment. The drug has not been evaluated in patients with severe hepatic impairment. Methylnaltrexone is administered subcutaneously in the upper arm, abdomen, or thigh. The usual frequency of administration is one dose every other day, as needed. No more than one dose should be administered in a 24-hour period. The recommended dose is 8 mg for patients weighing 38 to 61 kg (84– 135 lb) and 12 mg for patients weighing 62 to 114 kg (136–251 lb). For patients weighing less than 38 kg or more than 114 kg, a dosage of 0.15 mg/kg should be used. In patients with severe renal

Human papillomavirus vaccination: stabbing in the dark?

In September, the human papillomavirus (HPV) vaccine will become part of the UK’s immunisation programme. Initially, 12–13-year-old girls and a catch-up group of 17–18-year-old girls will be targeted in schools, with a three-dose vaccination schedule at 0, 1, and 6 months. Cervarix, a bivalent vaccine developed by GlaxoSmithKline, has been chosen in favour of Merck’s quadrivalent Gardasil. This vaccination programme could prevent 70–80% of cases of cervical cancer and over 90% of cases of genital warts, but its potential success depends on uptake. In a pilot study of just over 2800 schoolgirls in Manchester aged 12–13 years, overall uptake was 71% for the fi rst dose and 69% for the second. Uptake was lower among girls from less affl uent backgrounds and minority groups, and results from the third dose were not reported. Cancer Research UK reports these results as “encouraging”, but higher uptake would be desirable, particularly as cost-eff ectiveness models assume uptake greater than 80%. There are many possible explanations for poor uptake: fi rst, the logistical diffi culty of administering three doses of vaccine at specifi c times. Second, fears of the girls, their parents, and perhaps even teachers that the vaccination is dangerous. Third, concerns on moral or religious grounds that use of the HPV vaccine will promote sexual promiscuity. Fourth, girls, parents, and teachers lacking awareness of the advantages of immunity to HPV. Awareness is necessary for informed consent, which is a prerequisite for vaccination. However, a recent study reported that only 23% of 1348 Italian 14–24-year-old women knew that HPV can infect genital mucosa and had heard about cervical cancer. If these results can be extrapolated, it is worrying that most girls being off ered vaccination against HPV might have no concept of what the virus does, and certainly therefore no understanding of the benefi ts of immunity. If the programme is extended to include boys, conveying the value of herd immunity will be an even greater challenge than promoting individual immunity. Raising awareness of the link between HPV and cancer of the male genital tract, oral cavity, oropharynx, and larynx may be a more successful route for encouraging vaccination. The Department of Health has planned an advertising campaign, directed at young girls and their parents, to coincide with the fi rst injections. Hopefully, the multimedia messages will illuminate all those who are in the dark about the benefi ts of vaccination.

Respiratory arrest after low-dose fentanyl

Case report A 31-year-old man with facial trauma was brought to the universitybased hospital emergency department (ED). He reported that while working as a security guard 30 minutes prior, he was assaulted and struck in the left face with a monkey wrench. He complained of severe left facial pain, but denied any loss of consciousness, amnesia, vomiting, or neurologic defi cit. He denied any alcohol or recreational substance use. His past medical history was unremarkable, and he was taking no medications. Th e patient appeared awake, alert, and somewhat anxious, with normal vital signs. On examination, he had left malar fl attening, left periorbital ecchymosis and edema, and a 3-cm laceration of the eyelid. His left malar area was markedly tender and step-off depressions were palpated over the orbital rims. Computed tomography of his head and face demonstrated a tripod fracture of the left zygomatic body, fracture of the orbital fl oor, fracture of the anterior, posterior, and medial walls of the maxillary sinus. No intracranial abnormality was noted. An IV line was established to administer opioid analgesia per our department protocol for treating severe pain. Th e responsible physician elected to use fentanyl (total 200 μg/92 kg) because of its rapid onset, short duration, and titratability. Th e fi rst dose consisted 50 μg, which was approximately equal to 0.5 μg/kg. Two minutes after the administration of the fi rst dose of 50 μg of fentanyl, respiratory arrest with concomitant cyanosis ensued. Pulse oximetry revealed an oxygen saturation of 71% with no other changes in vital signs. Th e patient’s respirations were immediately assisted with 100% oxygen and a bag-valve-mask device and he was given 0.4 mg of naloxone IV. Within two minutes, spontaneous respirations resumed. During his resuscitation, his chest wall movement appeared normal while being ventilated, oxygen saturation remained above 90%, and glucose level was 97 mg/dL. His blood alcohol level was reported to be 144 mg/dL and a toxicologic screen performed on a previously obtained urine was reported as negative for opioids, benzodiazepines and barbiturates. Th e patient was monitored for two hours and recovered uneventfully. His laceration was repaired and he was transferred to a nearby facility for defi nitive treatment.

Pharmacokinetics (PK) and absolute bioavailability (F) of linezolid (L) in cystic fibrosis (CF) patients (PTS)

Introduction Methicillin- & vancomycin-resistant bacteria are increasingly responsible for CF exacerbations. L is highly active against these pathogens. We studied L first dose (FD) & steady-state (SS) PK in CF Pts. Methods CF pts received L-IV and then orally when indicated as part of their hospitalized clinical care. 12 blood samples & 4 timed urine aliquots were obtained over 24hrs after FD (2nd IV dose held) & 9 blood samples again at SS (dosed q8–12h). Quantitation of L and 2 inactive metabolites were determined by HPLC; standard non-compartment PK methodology was used. Results 10 pts (5 males) studied thus far; data analyzed for 7. Plasma L concentration-time curves reflect 2-compartment character. Mean(±)SD L PK after FD:t½-4.6 (1.9) hrs;Vd-0.67 (0.09) L/Kg; Cl-2.6 (1) ml/min/Kg. No differences were observed between FD & SS PK. ~18% of IV dose excreted in urine over 24hrs. Median L oral F was 110% of IV dose administered. L metabolites M25 & M23 accounted for ~24% & 5% of parent L plasma concentrations, respectively. These L PK data in CF are consistent with L PK data obtained in 39 non-CF Pts of similar age. Conclusions Our preliminary L CF PK data support conventional age-appropriate L dosing & employing a 1 to 1 conversion for IV to oral switch in the treatment of CF patients. Clinical Pharmacology & Therapeutics (2005) 77, P30–P30; doi: 10.1016/j.clpt.2004.12.006

Biodegradation and bioaccumulation of fenitrothion in rat liver.

The biodegradation of fenitrothion O,O-dimethyl-O-(3-methyl-4-nitro phenyl) phosphorothioate was investigated in rat liver after administration of various doses (5 mg/100 g body weight and 20 mg/100 g body weight) in acute treatment and 1 mg/100 g body weight in chronic treatment. High performance liquid chromatography of the pesticide and its metabolites formed in liver in acute treatment showed time-dependent sequential conversion of pesticide into three major metabolites within 24 h. These metabolites were separated and purified to homogenity by HPLC and characterized by IR spectroscopy as O,O-dimethyl-O-(3-methyl-4-amino phenyl) phsophorothioate (metabolite 1), O,O-dimethyl phosphorothioate (metabolite II) and O,O-dimethyl phosphate (metabolite III) in the fi rst dose (5 mg/100 g body weight). Metabolite II was found to be different in the second dose (20 mg/100 g body weight) and identified as O,O-dimethyl O-3-methyl-4-amino phenyl phosphate. The results with the fi rst dose indicated reduction of the nitro group in fenitrothion as step I followed by hydrolytic clevage of the P-O-aryl bond in metabolite I and oxidative desulphurylation of metabolite II. At higher dose (20 mg/100 g body weight) oxidative desulphurylation takes place as step II followed by hydrolysis of metabolite II. The bioaccumulation of fenitrothion within 60 days during chronic treatment showed no metabolite but continuous reduction in fenitrothion concentration, indicating excretion of pesticide and its products in urine and in faeces.

AMINOGLYCOSIDE DOSING IN BURN PATIENTS USING FIRSTDOSE PHARMACOKINETICS

Burn patients have altered aminoglycoside pharmacokinetics, which often result in subtherapeutic serum concentrations when these drugs are administered by conventional dosing (CD) methods. First-dose (FD) pharmacokinetic calculations can be used in these patients to determine an appropriate dosing regimen. We reviewed our experience with FD methods (12 patients) and CD methods (14 patients). Therapeutic levels were achieved more promptly in the FD group than in the CD group (44.4 +/- 8.1 vs. 97.1 +/- 12.5 hours; p < 0.005). Therapeutic serum concentrations were achieved with the first set of steady-state levels in 11% of CD patients and in 67% of FD patients (p < 0.005). The FD group required significantly fewer dosing changes (2.1 +/- 0.3) than did the CD group (3.7 +/- 0.7, p < 0.005). These data demonstrate that aminoglycoside dosing using first-dose pharmacokinetics results in improved maintenance of therapeutic serum concentrations compared with conventional methods in burn patients.

Single and Multiple Dose Pharmacokinetics of Methionyl Growth Hormone in Children with Idiopathic Growth Hormone Deficiency*

The pharmacokinetics (PK) of methionyl GH (metGH) were characterized in 20 newly diagnosed GH-deficient children (19 males; 12.9 +/- 3.3 yr old; initial height, 138.8 +/- 16.2 cm; weight, 32.1 +/- 13.1 kg) after the first dose (FD) of metGH and again after 4-5 weeks of multiple dosing (MD). All subjects received a total metGH dose of 0.3 mg/kg.week by sc administration, but were randomized to receive the drug daily (D; n = 12; dose, 0.043 mg/kg) or three times per week (TIW; n = 8; dose, 0.1 mg/kg). After drug administration, repeated blood samples (n = 14) were obtained over a 10-h period. Concentrations of metGH from each sample were determined using a monoclonal antibody radiometric assay (range of linearity, 0.5-40.0 ng/ml; coefficient of variation, less than 4%). Plasma concentration vs. time data were curve fit using a nonlinear weighted least squares algorithm which permitted calculation of the following PK parameters (mean +/- SEM; FD vs. MD group): elimination rate constant (0.23 +/- 0.04 vs. 0.25 +/- 0.04 h-1), absorption rate constant (0.43 +/- 0.05 vs. 0.48 +/- 0.04 h-1), elimination half-life (t1/2; 3.01 vs. 2.77 h), total plasma clearance (CL/F; 0.32 +/- 0.02 vs. 0.54 +/- 0.09 L/h.kg), and apparent volume of distribution (VDss/F; 2.2 +/- 0.14 vs. 3.15 +/- 0.28 L/kg). Both the CL/F and VDss/F of metGH were significantly greater when data from the entire study population were compared on the basis of FD vs. MD administration. With the exception of a larger VDss/F in subjects who received daily (3.6 +/- 0.4 L/kg) vs. TIW metGH (2.4 +/- 0.2 L/kg), no significant differences were found for the PK parameters between the D and TIW dosing groups. In all subjects, absorption of metGH was slow, with an average time to reach maximum concentration (Tmax) of 4.4 h and an absorption t1/2 that ranged from 1.4-1.8 h. Proportionality was also found between the dose and the area under the plasma concentration vs. time curve, suggesting dose-independent PK of metGH. Our data demonstrate that the PK of metGH after sc administration to children are markedly different from those previously reported in adults and, also, do not vary as a consequence of dosing schedule (i.e. D vs. TIW). The apparent increase in CL/F and VDss/F for met GH with multiple dosing may reflect concentration-dependent changes in plasma binding of the drug or, alternatively, represent the effect of increased body mass on the pharmacokinetics of GH.

THE CLINICAL PHARMACOLOGY OF IMIPENEM (IMP) AND CILISTATIN (CIL) IN PREMATURE INFANTS

IMP/CIL is a new combination β-lactam antibiotic which possesses potent in vitro activity against a broad range of pathogens commonly isolated from premature (P) and newborn infants. To assess dosing requirements, P were assigned to 10, 15, 20 or 25 mg/kg IMP/CIL intravenously over 15 to 40 min either as single or multiple doses. 30 P (670-1890 gm) from 24.5-36 weeks gestation were studied. All were studied during the first dose (FD); 12 were restudied after at least 10 doses (SS) given q12h. All studies were performed during the first week of life. Multiple blood and urine samples (over 8-12 hrs) were obtained for the determination of IMP/CIL by HPLC. Pharmacokinetic (PK) analysis was performed using standard non-compartmental methods. Total (n=29) FD PK revealed mean (±SD) IMP: 11/2=2.4(0.3), Vdss=0.5(0.1)L/kg, CI=47(12) ml/min/1.73m2 and CIL: t1/2=8(2.8), Vdss=0.4(0.1)L/kg, and CI=10.5(3.5) ml/min/1.73m2. IMP/CIL renal CI averaged 8.7(4.2) and 4.0(2.5) ml/min/1.73m2, respectively. No differences were observed in PK parameters (except AUC) for the different doses studied or between IMP FD and SS evaluations. In contrast, SS CIL AUC and t1/2 were decreased and body CI increased from FD (p<0.02). IMP/CIL AUC correlated directly with dose administered: FD IMP r=0.74 and CIL r=0.64. Peak IMP/CIL concentrations averaged 23.6 and 32.1 mg/L after 10 mg/kg FD increasing linearly over the dose range studied. A direct relationship between post conceptual age (PCA) and FD IMP/CIL body CI(r=0.61/0.55) and renal CI (r=0.31/0.68) was observed. No drug related toxicities were observed in any P. Depending on PCA, doses should range from 15 to 25 mg/kg administered q12h to maintain therapeutic peak and trough IMP serum concentrations. CIL body CI increases rapidly and to a greater extent than IMP during the first week of life.

364 PHAEMACOKINETIC EVALUATION OF TRIMETHOPRIM-SULFAMETH-OXAZOLE(TMP-SMX) IN PATIENTS WITH CYSTIC FIBROSIS(CF)

The first dose (FD) and steady state (SS) pharmacokinetics of orally administered TMP-SMX was evaluated in 15 patients with CF. The biodisposition of the TMP and SMX were regulated independently and no fixed ratio of the TMP to SMX was maintained. The FD and SS pharmacokinetic parameters for TMP were determined using a single compartment model. Data are given in the table below. When the FD and SS data for SMX were similarly analyzed using either a one- or two-compartment model large interindividual differences in biodisposition were observed. At least half the patients were found to have saturable SMX elimination pathways and total SMX absorption was found to increase markedly with continued therapy (AUCSS>AUCFD;∼3-fold). These results suggest that the biodisposition of TMP-SMX in patients with CF is markedly different from that observed in unaffected individuals. Because of the independent biodisposition of TMP and SMX and the large interindividual differences in SMX elimination kinetics, the administration of these drugs in CF patients may be more effective as single agents.