Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients

OBJECTIVE: To assess the pharmacokinetics of chronic methylprednisolone therapy in renal transplant patients receiving double-drug (methylprednisolone and azathioprine) and triple-drug (methylprednisolone, azathioprine, and cyclosporine) immunosuppression. DESIGN: Parallel, randomized trial. PATIENTS: Fourteen renal transplant recipients (aged 29–65 y) evaluated in a public, university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone via a 10–20-minute intravenous infusion. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate pharmacokinetic parameters for this drug. RESULTS: The mean daily methylprednisolone dosage was 19 ± 19 mg in the double-drug group and 9 ± 2 mg in the triple-drug group. Mean serum creatinine concentrations were 124 ± 44 and 124 ± 27 μmol/L, respectively. Mean methylprednisolone clearances were similar in both groups: 405 ± 205 (double-drug) and 373 ± 365 mL/h/kg (triple-drug) (p>0.05). Mean steady-state volume of distribution was 1.5 ± 0.8 L/kg in the double-drug group and 1.3 ± 0.8 L/kg in the triple-drug group (p>0.05). Plasma half-life ranged from 1.7 to 4.3 h (mean 2.7) in the double-drug group versus 1.4 to 3.4 h (mean 2.6) in the triple-drug group (p>0.05). CONCLUSIONS: These data indicate that cyclosporine had no definitive influence on methylprednisolone disposition. The results reveal a wide variation in methylprednisolone metabolism in renal transplant recipients receiving either a double- or triple-drug immunosuppressive regimen. Typically, methylprednisolone is prescribed according to a standardized dosing protocol that assumes minimal interpatient variation. Therefore, the pharmacokinetic variability noted in this study may have important clinical implications regarding the development of chronic toxicity (e.g., osteoporosis, hypothalamic-pituitary-adrenal suppression) and the attainment of successful immunosuppression.

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Homocysteine in the Plasma of Renal Transplant Recipients: Effects of Cofactors for Methionine Metabolism

Clinical Science ◽

10.1042/cs0610743 ◽

1981 ◽

Vol 61 (6) ◽

pp. 743-749 ◽

Cited By ~ 97

Author(s):

D. E. L. Wilcken ◽

Vatsala J. Gupta ◽

A. K. Betts

Keyword(s):

Folic Acid ◽

Amino Acid ◽

Renal Transplant ◽

Serum Creatinine ◽

Vitamin B12 ◽

Normal Subjects ◽

Serum Folate ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Erythrocyte Folate

1. Homocysteine which is formed during the metabolism of methionine is readily oxidized and is measured by the amino acid analyser as cysteine—homocysteine mixed disulphide and homocystine. We measured plasma amino acid concentrations after an overnight fast in 27 stable long-term renal transplant recipients and 25 age-and sex-matched normal subjects with particular emphasis on sulphur-containing amino acids. 2. Plasma cysteine—homocysteine mixed disulphide was increased in the patients (mean 6.0 ± sd 3.2 μmol/l; normal 3.1 ± 0.9 μmol/l, P < 0.001) and homocystine was detectable in low concentration (< 1.0 μmol/l) in 24; the elevation in cysteine—homocysteine was related to serum creatinine (r = 0.60, P < 0.002). Cystine was also increased (91.6 ± 29.3 μmol/l; normal subjects 64.0 ± 16.7 μmol/l, P < 0.001), but methionine concentrations were normal. 3. When pyridoxine, folic acid and vitamin B12, cofactors for homocysteine metabolism, were administered sequentially to 11 arbitrarily selected transplant recipients cysteine—homocysteine decreased from 7.3 ± 2.1 to 4.3 ± 0.8 μmol/l (P < 0.001) and homocystine became undetectable. the response coincided with the giving of folic acid and occurred without alteration in serum creatinine and with normal serum folate and vitamin B12 concentrations. 4. in eight patients in whom pretreatment erythrocyte folate was measured, folic acid therapy reduced cysteine—homocysteine from 9.0 ± 3.1 to 5.4 ± 1.6 μmol/l over a 4 week period (P < 0.001), the largest response being in the one patient with subnormal erythrocyte folate; values were in the low-normal or normal range in the other seven. 5. We conclude that plasma homocysteine is increased in renal transplant recipients when serum creatinine is only moderately elevated and that the homocysteine concentrations are decreased by treatment with folic acid, suggesting that both reduced homocysteine excretion and relative shortages of folic acid are responsible.

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Serum Cystatin C as a Determinant of Fasting Total Homocysteine Levels in Renal Transplant Recipients with a Normal Serum Creatinine

Journal of the American Society of Nephrology ◽

10.1681/asn.v101164 ◽

1999 ◽

Vol 10 (1) ◽

pp. 164-166 ◽

Cited By ~ 1

Author(s):

ANDREW G. BOSTOM ◽

REGINALD Y. GOHH ◽

LINDA BAUSSERMAN ◽

DAVID HAKAS ◽

PAUL F. JACQUES ◽

...

Keyword(s):

Renal Transplant ◽

Serum Creatinine ◽

Cystatin C ◽

Normal Serum ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Serum Cystatin C ◽

Serum Cystatin ◽

Total Homocysteine ◽

Plasma Total Homocysteine

Abstract. Serum creatinine, a surrogate for both renal function and homocysteine generation, is an important determinant of fasting plasma total homocysteine levels in stable renal transplant recipients. In this study, it is hypothesized that among stable renal transplant recipients with normal creatinine levels (i.e., ≤ 1.5 mg/dl), serum cystatin C, a more sensitive indicator of GFR, would better predict fasting total homocysteine levels compared with serum creatinine. Fasting plasma total homocysteine, folate, vitamin B12, and pyridoxal 5′-phosphate levels, along with serum cystatin C, creatinine, and albumin levels, were determined in 28 consecutive renal transplant recipients (mean age 47 ± 14 yr; 60.7% men) with stable allograft function, whose serum creatinine was ≤1.5 mg/dl. General linear modeling with analysis of covariance revealed that serum cystatin C was independently predictive (partial R = 0.494; P = 0.023) of fasting total homocysteine levels after adjustment for age, gender, vitamin status, albumin, and creatinine levels. In contrast, creatinine levels were not predictive of fasting total homocysteine levels in this model (P = 0.110) or an identical model that excluded cystatin C (P = 0.131). Serum cystatin C levels may reflect subtle decreases in renal function that independently predict fasting total homocysteine levels among stable renal transplant recipients with a normal serum creatinine.

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