The Pharmacokinetics and Colonic Tissue Concentrations of Cyclosporine After IV, Oral, and Enema Administration I.

William

Sandborn,

MD, Resa

This

study

Richard

E. Chase,

and

MD,

MD,

Ralph

Steven

E. Cutler,

C. F’orland,

PharmD,

MD

colonic tissue concentrations of enemas with conventional intravenous were enrolled in a prospective crossover cyclosporine on four separate occasions, as a water enema, and once IV. Cyclosporine in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 ± 7% (mean ± SD) for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 ± 17,251 ng/g (mean ± SD) for the IV dose, 2797 ± 1812 ng/g for the oral dose, 21,727 ± 14.090 ng/g for the oil enema, and 25,318 ± 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after IV or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine-retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left-sided colitis. Because cyclosporine administered by the IV route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse IV cyclosporine should be tried for patients with severe ileitis and colitis. cyclosporine

compares

M. Strong,

pharmocokinetic

parameters and or water-retention (IV) and oral dosing. Five medical students study. All subjects received a single dose of once orally, once as an olive-oil enema, once concentration was measured in blood and administered

by

olive-oil

C yclosporine

is a potent suppressor of cell-mediated immunity, that is widely used in organ transplantation. Current reports show that cyclosporine provides effective treatment for ulcerative colitis and Crohn’s disease.#{176} The immunologic basis for this response is not well understood, but it lends support to theories of antibody-mediated cytotoxicity and cell-mediated immune dysfunction at the level of the intestinal mucosa.#{176}1#{176} If the immune effect is local, then the colonic tissue concentration of cyclosporine may correlate with clinical response. Measurement of cyclosporine concentration in

From

the

Jerry

L. Peths

Memorial

Veterans

Strong, Chase, and Pathology. Sections

Cutler). Departments of Gastroenteroiogy,

Pharmacology,

Linda

and Cutler), Pharmaceutical (111N),

Street,

76

Jerry Loma

Loma

University

Loma Linda, California. Corporation. L. Pettis

Linda,

Address Memorial

School

1991;31:76-80

Sandborn,

Medicine and and Clinical (Drs.

Forland

by a grant from Sandoz

for reprints: Veterans

(Drs.

of Medicine

Supported

CA 92357.

#{149} J Clin Pharmacol

Hospital of Internal Nephrology,

Ralph

Hospital,

E. Cutler, 11201

MD

Benton

human tissue obtained at autopsy has been described.11-14 Reid11 found colon concentrations among the highest in the body. Gyclosporine concentration in tissue obtained by biopsy from living humans has not been described. Concerns about toxicity have limited the use of cyclosporine in patients with inflammatory bowel disease to the 10 to 15% of patients in whom standard therapy fails.156 In attempts to minimize toxicity, cyclosporine has been applied topically by water-retention enema in patients with Grohn’s proctosigmoiditis and distal chronic ulcerative colitis, with some success.178 Blood cyclosporine concentrations after enema administration were minimal in these studies. Enema administration of cyclosporine using a hydrophobic medium such as olive-oil has not been reported. Since cyclosporine is hydrophobic, it is possible that oil enema delivery may increase absorption. This study compares the pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive-oil or water-retention enemas

CYCLOSPORINE

ENEMA

with conventional IV and oral dosing in healthy human volunteers. Different pharmacokinetic characteristics for various types of cyclosporine dosing may have implications for minimizing toxicity when cyclosporine is used to treat inflammatory bowel disease.

METHODS Subjects.

Paid,

medical

student

volunteers

on

clini-

cal assignment at the Jerry L. Pettis Memorial Veterans Hospital were admitted to the study after giving written informed consent to a protocol approved by the local institutional review board. The five subjects (3 men and 2 women) ranged in age from 25 to 41

years;

their

body

weight

ranged

from

47 to 92

kg. According to their histories, findings on physical examination, and results of flexible sigmoidoscopy with biopsy, the subjects were healthy. Gomplete blood counts, serum chemistry panels, and human chorionic gonadotropin levels (women only) were obtained. Subjects were excluded if they had laboratory evidence of pregnancy or of hepatic or renal dysfunction, or endoscopic or histologic evidence of gastrointestinal

disease.

Drug Administration. Cyclosporine administered as a single dose on sions

during

I week

apart.

the

study

orally as the (100 mg/mL).

No

other

period.

four

medications

The

commercially The second

first

(5 mg/kg) different were dose was

available and third

was

occataken given

oral solution doses were

given rectally as an enema, which was prepared immediately before administration. The enema for the second dose was prepared by mixing the oral solution in 60 mL of olive oil, and the third dose was prepared by suspending oral solution in 60 mL of water along with 5 g of sorbitol and 500 mg of carboxymethyl cellulose to form an aqueous suspension. The subjects were instructed to remain supine for 30 minutes and to retain the enema for at least 2 hours. The fourth dose was given by IV over 2 hours as the commercially available concentrate for injection (50 mg/mL) diluted in .9% sodium chloride. Blood Cyclosporine Assay. On each study day, venous blood samples were drawn from an IV catheter into evacuated tubes containing EDTA. Samples were obtained before cyclosporine administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, and 25 hours after cyclosporine administration. Whole blood samples were stored at 2#{176}C until assayed. Blood concentrations of cyclosporine were determined

using

a specific

CYCLO-Trac Stillwater,

monoclonal SP

RIA

radioimmunoassay, (INCSTAR

MN).19

IMMUNOSUPPRESSIVE

AGENTS

Corporation,

PHARMACOKINETICS

Tissue Cyclosporine Assay. On each study day, a flexible sigmoidoscopy examination limited to 12 to 18 cm was performed without prior laxatives or enemas in subjects 8 hours after administration of the drug was begun, and five mucosal pinch biopsy specimens were obtained. Because the amount of tissue that can be obtained safely by endoscopic biopsy is small, tissue biopsy was done at the time maximal tissue concentration was most likely to be reached, 8 hours after dosing,2#{176} to ensure that enough cyclosporine would be present to assay. One biopsy specimen was sent for histologic examination. The other four biopsy specimens were immediately combined, weighed, and washed in saline to remove any drug adhering to the surface of the tissue. The tissue was cut into fragments, mixed with 2 mL of 95% methanol, and homogenized with an ultrasonic probe. The organic phase was separated, and the extraction process was repeated using 2 mL of chloroform:methanol (2:1 v:v) solution. The organic phases were mixed, the solvent was evaporated, and the dry residue was stored at 2#{176}C.The dried samples were reconstituted with .5 mL of 95% methanol and assayed as described for blood cyclosporine concentrations. Colonic

Data Analysis. For this study, the maximum blood cyclosporine concentration (Cmax) and the time (Tmax) to reach Cmax were defind as the highest measured blood cyclosporine concentration and the time of the sample, respectively. The following pharmacokinetic parameters were calculated using standard equations21: area under the blood cyclosporine concentration versus time curve (AUC), bioavailability (F), blood elimination half-life (T#{189}), and blood cyclosporine clearance (GLb). These calculations were performed using a computer program developed in our laboratory. Statistical Analysis. A medical database management program, MRTOD (Retriever Data Systems, Seattle, WA), and Crunch software interactive statistical package, CRISP (Crunch Software Corporation, Oakland, CA), were used. Comparisons among IV, oil enema, water enema, and oral administration

of cyclosporine

were

analysis of variance Differences were .30). The correlation, r, of colonic tissue

concentration .55 for the

with enema oil enemas and

retention .58 for the

blood at the

counts ‘and completion

serum of the

chemistry study were

t-tests

was

low,

enemas.

panels normal.

obtained

DISCUSSION The pharmacokinetic parameters Tmax, Cmax, AUC, and T#{189} calculated for IV and oral dosing in our study are comparable with those reported in the literature.22 The mean bioavailability of 18% for oral dosing is less than the average of 25 to 30%, but is within the range found by others. The minimal absorption of cyclosporine administered as a water enema is not surprising. Previous studies of cyclosporine enemas using water, sorbitol, and carboxymethylcellulose,17 and water, mesalazine, and betamethason&8 found very low blood concentrations. Brynskov17 suggested that the lack of absorption was due to the hydrophilic delivery of a hydrophobic

I After

IV, Enema,

and Oral Doses

Oil Enema

Water Enema

16± 15 39 ± 61

oil

=

water.

P

1.0

The pharmacokinetics and colonic tissue concentrations of cyclosporine after i.v., oral, and enema administration.

This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive-oil or water-retention enemas w...
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