Influences of Urinary pH on Ciprofloxacin Pharmacokinetics in Humans and Antimicrobial Activity In Vitro versus Those of Sparfloxacin

Marika Kamberi; Kimiko Tsutsumi; Tsutomu Kotegawa; Koichi Kawano; Koichi Nakamura; Yoshihito Niki; Shigeyuki Nakano

doi:10.1128/AAC.43.3.525

DOI: 10.1128/AAC.43.3.525

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Fig. 1.
Changes in the urinary pH over 24 h in healthy subjects treated with ammonium chloride (●), sodium bicarbonate (▵), or water (○). Values represent means ± SDs for nine subjects.

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Table 1.

Influence of urinary pH on ciprofloxacin pharmacokinetics in plasma: a comparison between pharmacokinetic variables on three separate occasions under different conditions of urinary pH

Pharmacokinetic variables^a	Result^b(SD) under treatment with:
Pharmacokinetic variables^a	NaHCO₃	NH₄Cl	H₂O
C_max(μg/ml)	1.729 (0.33)	1.506 (0.238)	1.804 (0.421)
T_max(h)	1.2 (0.2)	1.3 (0.5)	1.0 (0.4)
t_1/2(h)	4.6 (1.6)	4.3 (1.1)	4.2 (0.8)
AUC (μg · h/ml)	5.147 (0.680)	5.320 (0.770)	5.649 (0.884)
CL/F(liters/h)	37.971 (6.711)	39.011 (5.599)	37.464 (5.194)
V/F(liters)	248.762 (78.602)	234.484 (46.28)	223.377 (37.52)
CL_R(liters/h)	16.08 (3.02)	16.78 (2.67)	16.31 (2.67)
Ae (mg)	82.4 (16.5)	88.4 (14.5)	90.53 (9.8)

↵a T_max, time to peak concentration in plasma; t_1/2, apparent elimination half-life; AUC, area under the plasma concentration-time curve (0 to 24 h); CL/F, apparent total body clearance;V/F, apparent volume of distribution; CL_R, renal clearance; Ae, amount of unchanged drug excreted.
↵b The pharmacokinetic parameters were calculated according to a two-compartment open model with first-order absorption. ANOVA was utilized to describe significant differences in the pharmacokinetic parameters and urinary pH; all differences were not significant.

Table 2.

Amount of unchanged drug excreted into urine at various time periods after treatment with ammonium chloride, sodium bicarbonate, or water^a

Collection period (h)	Amt (mg) of unchanged drug (SD) under treatment with:
Collection period (h)	NaHCO₃	NH₄Cl	H₂O
0–2	22.426 (9.679)	24.756 (8.564)	26.251 (5.156)
2–4	20.099 (6.690)	19.877 (5.327)	21.988 (9.145)
4–6	12.763 (3.253)	12.695 (5.696)	13.700 (3.366)
6–8	8.220 (2.015)	11.098 (5.958)	9.314 (3.884)
8–12	10.935 (2.269)	10.116 (2.546)	10.598 (2.410)
12–24	9.899 (2.604)	8.304 (3.246)	8.608 (3.927)

↵a ANOVA was utilized to describe significant differences; all differences were not significant.

Table 3.

Influence of pH and Ca²⁺ and Mg²⁺cations on the MICs of ciprofloxacin and sparfloxacin

Strain and drug	MIC [μg/ml (fold increase)] in broth^a at pH:
	8.0 (MHB-A)	7.2				5.8 (MHB-A)
	8.0 (MHB-A)	MHB-A	MHB-B	MHB-C	MHB-D	5.8 (MHB-A)
E. coli NIHJ JC-2
Ciprofloxacin	0.016	0.031 (2)	0.031 (2)	0.063 (4)	0.063 (4)	0.125 (8)
Sparfloxacin	0.008	0.031 (4)	0.031 (4)	0.063 (8)	0.063 (8)	0.25 (31)
P. aeruginosa ATCC 27853
Ciprofloxacin	0.50	0.50 (1)	0.50 (1)	0.50 (1)	1 (2)	2 (4)
Sparfloxacin	0.50	2 (4)	2 (4)	4 (8)	4 (8)	8 (16)

↵a MHB-A, MHB with concentrations of Ca²⁺ and Mg²⁺ of 25 and 12.5 mg/liter, respectively; MHB-B, MHB with concentrations of Ca²⁺ and Mg²⁺ of 50 and 25 mg/liter, respectively; MHB-C, MHB with concentrations of Ca²⁺ and Mg²⁺ of 125 and 62.5 mg/liter, respectively; MHB-D, MHB with concentrations of Ca²⁺ and Mg²⁺ of 250 and 125 mg/liter, respectively.

Table 4.

Influence of human urine on the in vitro activities of ciprofloxacin (CPFX) and sparfloxacin (SPFX) against E. coliNIHJ JC-2 and P. aeruginosa ATCC 27853

Subject no.	NH₄Cl treatment							NaHCO₃ treatment
	pH	Concn [mg/liter (fold increase)] of:		MIC [μg/ml (fold increase)] for:				pH	Concn [mg/liter (fold increase)] of:		MIC [μg/ml (fold increase)] for:
		Ca²⁺	Mg²⁺	E. coli NIHJ JC-2		P. aeruginosa ATCC 27853			Ca²⁺	Mg²⁺	E. coli NIHJ JC-2		P. aeruginosa ATCC 27853
		Ca²⁺	Mg²⁺	CPFX	SPFX	CPFX	SPFX		Ca²⁺	Mg²⁺	CPFX	SPFX	CPFX	SPFX
1	5.36	320 (4)	145 (4.3)	0.25 (4)	0.25 (4)	0.125	2 (2)	6.28	86	61	0.063	0.063	0.50 (2)	1
2	5.40	220 (4)	120 (1.2)	0.125 (4)	0.125 (4)	0.125 (1)	2 (4)	6.37	58	100	0.031	0.031	0.125	0.50
3	5.27	200 (2)	80	0.50 (8)	0.50 (8)	0.125 (2)	2 (4)	6.10	97	105 (1.3)	0.063	0.063	0.063	0.50
4	6.39	200 (2)	135 (2.5)	0.063 (4)	0.063 (4)	0.25 (2)	0.50 (4)	7.78	43	53	0.016	0.016	0.125	0.125
5	6.03	240 (2)	145 (1)	0.125 (2)	0.25 (4)	0.125	2 (4)	7.28	225	110	0.063	0.063	0.50 (4)	0.50
6	6.12	200 (2)	54 (1)	0.50 (8)	0.50 (8)	0.25 (1)	2 (1)	7.14	13	44	0.063	0.063	0.25	2
7	6.13	270 (7)	130 (1.3)	0.125 (1)	0.25 (1)	0.25 (1)	2 (1)	7.43	41	100	0.125	0.25	0.25	2
8	5.79	80 (1)	70 (1)	0.125 (2)	0.125 (2)	0.25	1 (2)	6.35	79	85	0.063	0.063	0.50 (2)	0.50
9	5.30	56 (1)	33 (2)	0.50 (31)	0.50 (31)	0.50 (1)	2 (4)	8.01	36	18	0.016	0.016	0.50	0.25
Mean (SD)	5.75 (0.43)	178.4 (97)	101.3 (40.1)					6.97 (0.71)	75.3 (58.6)	75.1 (30.5)
Range	5.27–6.39	56–320	33–145	0.063–0.50	0.063–0.50	0.125–0.50	0.50–2	6.84–8.1	13–225	18–110	0.016–0.125	0.016–0.25	0.125–0.50	0.125–2