Nasir Idkaidek

Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status

BackgroundVitamin D is cutaneously synthesized following sun exposure (vitamin D3) as well as it is derived from dietary intake (vitamin D3 and D2). Vitamin D2 and D3 are metabolized in the liver to 25-hydroxyvitamin D (25(OH)D). This metabolite is considered the functional indicator of vitamin D stores in humans. Since Jordan latitude is 31°N, cutaneous synthesis of vitamin D3 should be sufficient all year round. However, many indications reveal that it is not the case. Thus, this study was conducted to determine the 25(OH)D status among Jordanians.MethodsThree hundred healthy volunteers were enrolled in a cross sectional study; 201 females and 99 males. 25(OH)D and calcium concentrations were measured by enzyme linked immunosorbent assay and spectroscopy techniques, respectively. All participants filled a study questionnaire that covered age, sex, height, weight, diet, and dress style for females. Females were divided according to their dress style: Western style, Hijab (all body parts are covered except the face and hands), and Niqab (all body parts are covered including face and hands).ResultsThe average plasma 25(OH)D levels in males and females were 44.5 ± 10.0 nmol/l and 31.1 ± 12.0 nmol/l, respectively. However, when female 25(OH)D levels were categorized according to dress styles, the averages became 40.3, 31.3 and 28.5 nmol/l for the Western style, Hijab and Niqab groups, respectively. These 25(OH)D levels were significantly less than those of males (p < 0.05, 0.001, 0.001, respectively). In addition, the plasma 25(OH)D levels of the Western style group was significantly higher than those of Hijab and Niqab groups (p < 0.001). Furthermore, dairy consumption in males was a positive significant factor in vitamin D status. Even though calcium concentrations were within the reference range, the Hijab and Niqab-dressed females have significantly less plasma calcium levels than males (p < 0.01).ConclusionsVery low plasma 25(OH)D levels in females wearing Hijab or Niqab are highly attributed to low sunlight or UVB exposure. In addition, most of males (76%) and Western style dressed females (90%) have 25(OH)D concentrations below the international recommended values (50 nmol/l), suggesting that although sun exposure should be enough, other factors do play a role in these low concentrations. These findings emphasize the importance of vitamin D supplementation especially among conservatively dressed females, and determining if single nucleotide polymorphisms of the genes involved in vitamin D metabolism do exist among Jordanians.

Saliva versus plasma pharmacokinetics: theory and application of a salivary excretion classification system.

The aims of this work were to study pharmacokinetics of randomly selected drugs in plasma and saliva samples in healthy human volunteers, and to introduce a Salivary Excretion Classification System. Saliva and plasma samples were collected for 3-5 half-life values of sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin after oral dosing. Saliva and plasma pharmacokinetic parameters were calculated by noncompartmental analysis using the Kinetica program. Effective intestinal permeability (Peff) values were estimated by the Nelder-Mead algorithm of the Parameter Estimation module using the SimCYP program. Peff values were optimized to predict the actual average plasma profile of each drug. All other physicochemical factors were kept constant during the minimization processes. Sitagliptin, cinacalcet, metformin, tolterodine, HCT, azithromycin, rosuvastatin and cloxacillin had salivary excretion with correlation coefficients of 0.59-0.99 between saliva and plasma concentrations. On the other hand, montelukast, lornoxicam, diacerhein, losartan and tamsulosin showed no salivary excretion. Estimated Peff ranged 0.16-44.16 × 10(-4) cm/s, while reported fraction unbound to plasma proteins (fu) ranged 0.01-0.99 for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.11-13.4, in agreement with drug protein binding and permeability. A Salivary Excretion Classification System (SECS) was suggested based on drug high (H)/low (L) permeability and high (H)/low (L) fraction unbound to plasma proteins, which classifies drugs into 4 classes. Drugs that fall into class I (H/H), II (L/H) or III (H/L) are subjected to salivary excretion, while those falling into class IV (L/L) are not. Additional data from literature was also analyzed, and all results were in agreement with the suggested SECS. Moreover, a polynomial relationship with correlation coefficient of 0.99 is obtained between S* and C*, where S* and C* are saliva and concentration dimensionless numbers respectively. The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion. Future work is planned to test these initial findings, and demonstrate SECS robustness across a range of carefully selected (based on physicochemical properties) drugs that fall into classes I, II or III.

Effect of Microgravity on the Pharmacokinetics of Ibuprofen in Humans

The pharmacokinetics of ibuprofen were studied under microgravity (μG) conditions and compared with those at normal gravity (1G) in humans. Six healthy human volunteers were given 600 mg oral dose ibuprofen during 1‐day simulated μG antiorthostatic bed rest position, then at normal position (1G) in a sequential design with 7 days washout time. Saliva and plasma samples were obtained up to 8 hours after dosing. Ibuprofen was not detected in all saliva samples. Pharmacokinetic parameters in plasma were calculated by either noncompartmental analysis or a 1‐compartment model using the Kinetica program. Absorption kinetic parameters were then predicted by ADAM and PE modules using the Simcyp program. Results have showed an increased rate of ibuprofen dissolution and absorption and hence faster onset of action under μG conditions. However, rate of drug elimination and bioavailability was not affected by μG, suggesting no need for dose adjustment.

The hydrolysis kinetics of monobasic and dibasic aminoalkyl esters of ketorolac

Six aminoethyl and aminobutyl esters of ketorolac containing 1-methylpiperazine (MPE and MPB), N-acetylpiperazine (APE and APB) or morpholine (ME and MB), were synthesized and their hydrolysis kinetics were studied. The hydrolysis was studied at pH 1 to 9 (for MPE, APE and ME) and pH 1 to 8 (for MPB, APB and MB) in aqueous phosphate buffer (0.16 M) with ionic strength (0.5 M) at 37°C. Calculation of kobs, construction of the pH-rate profiles and determination of the rate equations were performed using KaleidaGraph® 4.1. The hydrolysis displays pseudo-first order kinetics and the pH-rate profiles shows that the aminobutyl esters, MPE, APB and MB, are the most stable. The hydrolysis of the ethyl esters MPE, APE and ME, depending on the pH, is either fast and catalyzed by the hydroxide anion or slow and uncatalyzed for the diprotonated, monoprotonated and nonprotonated forms. The hydrolysis of the butyl esters showed a similar profile, albeit it was also catalyzed by hydronium cation. In addition, the hydroxide anion is 105 more effective in catalyzing the hydrolysis than the hydronium cation. The hydrolysis pattern of the aminoethyl esters is affected by the number and pKa of its basic nitrogen atoms. The monobasic APE and ME, show a similar hydrolysis pattern that is different than the dibasic MPE. The length of the side chain and the pKa of the basic nitrogen atoms in the aminoethyl moiety affect the mechanism of hydrolysis as the extent of protonation at a given pH is directly related to the pKa.

A Retrospective, Open-Label Analysis of the Population Pharmacokinetics of a Single 10-mg Dose of Loratadine in Healthy White Jordanian Male Volunteers

BACKGROUND Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H(1)-receptor antagonist activity. Loratadine 10-mg tablets have been reported to be rapidly absorbed after once-daily administration for 10 days in healthy adult subjects, with a T(max) of 1.3 hours for loratadine and 2.5 hours for its major active metabolite, descarboethoxyloratadine. The t(1/2) in normal adult subjects has been reported to be 8.4 hours (range, 3-20 hours) for loratadine and 28 hours for its metabolite. OBJECTIVE The aim of this study was to determine the population pharmacokinetics of loratadine after oral administration. METHODS A retrospective analysis was conducted of prior noncompartmental analysis results from healthy white Jordanian male subjects who participated in 2 pharmacokinetic studies. After a 10-hour overnight fast, a single 10-mg loratadine tablet was administered orally followed by 240 mL of water. Blood samples were collected before dosing and at 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours after dosing. Mean and population plasma level profiles were examined. The calculated primary and secondary pharmacokinetic parameters were V(d)/F, k(e), absorption rate constant, lag time, distribution rate constant, redistribution rate constant, T(max), and C(max). RESULTS A total of 72 healthy male subjects with a mean (SD) age of 23 (3.57) years participated in the 2 studies. The analytical method was linear over the concentration range from 0.10 to 20.00 ng/mL (r > 0.999). The lower limit of quantitation was 0.1 ng/mL with 95% accuracy. Precision, expressed as %CV, was 7.44%. Intraday accuracy ranged from 91.9% to 97.2% at high and low quality control levels, respectively. Interday accuracy ranged from 93.57% (%CV, 4.35%) to 98.78% (%CV, 5.78%), respectively. Population ke, t(1/2), absorption rate constant, and absorption t(1/2) were 0.19 hour(-1), 3.65 hours, 1.31 hours(-1), and 0.53 hour, respectively. Distribution rate constant, redistribution rate constant, and lag time were 0.31 hour(-1), 0.02 hour(-1), and 0.32 hour, respectively. The noncompartmental estimate for C(max) was 3.02 ng/mL, which occurred at 1.30 hours, with a t(1/2) of 5 hours and a k(e) of 0.14 hour(-1). No adverse events were recorded during the study. CONCLUSION The population t(1/2) for loratadine was 3.65 hours in this group of healthy white Jordanian male volunteers, shorter than that observed in previous research.

Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems.

UNLABELLED The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. CONCLUSION The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding.

Saliva vs. Plasma Bioequivalence of Paracetamol in Humans: Validation of Class I Drugs of the Salivary Excretion Classification System

AIMS To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.

Effect of Replicate Design on Drug Variability and Bioequivalence in Humans

The purpose of this study is to investigate the effect of using replicate design on the intra/inter subject variability and bioequivalence of drugs in healthy volunteers. Model drugs used for analysis were amoxicillin/clavulanic acid combination. 24 healthy subjects participated in this study using 4-phase replicate cross over design. Individual disposition kinetic parameters of areas under plasma concentrations (AUC0-t) and maximum concentration (Cmax) were calculated by non-compartmental analysis using Kinetic program V 4.2 using all phases. The 90 % confidence intervals for log-transformed AUC0-t and Cmax were calculated for phases I & II; then for phases I, II and III; and for phases I, II, III and IV respectively. The intra and inter-subject variability values did not show a trend to decrease by the increase in phases included in analysis in both drugs and for both parameters. In addition, the 90 % confidence intervals for log-transformed AUC0-t and Cmax passed the 80-125 % limit range in both drugs for all phase combinations, even though Cmax variability was shown high for clavulanic acid. However, individual bioequivalence was shown for AUC and not shown for Cmax of both drugs. These results suggest not using replicate design as an approach to show the high inter/intra subject variability of highly variable drugs and hence justify wider acceptance limits of 75-133 % as recommended by the draft EMEA guideline. Literature information about drug high variability should be adequate to justify using wider acceptance limits of 75-133%.

Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System

Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used.

Bioequivalence of two pregabalin 300 mg capsules (Neurexal and Lyrica®) in healthy human volunteers.

The pharmacokinetics of 2 brands of pregabalin 300 mg capsules were compared in 23 healthy human volunteers after a single oral dose in a randomized cross-over study. The study protocol was prepared with relevance to the requirements set in the US FDA and the EMA guidances for conduction of bioequivalence studies. Reference (Lyrica(®), Pfizer, France) and test (Neurexal, Pharmaline, Lebanon) products were administered to fasted volunteers. Blood samples were collected up to 48 h and assayed for pregabalin using a validated LC-MS/MS method. The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, Tmax, T1/2 and elimination rate constant were determined from plasma concentration-time profile by non-compartmental analysis method using WinNonlin V5.2. The analysis of variance did not show any significant difference between the 2 formulations and 90% confidence intervals fell within the acceptable range for bioequivalence: 80-125%. It was concluded that the 2 brands exhibited comparable pharmacokinetic profiles and that Pharmalines Neurexal is bioequivalent to Lyrica(®) of Pfizer, France.